Introduction and Key Concepts

KCTD16 (Potassium Channel Tetramerization Domain-containing protein 16) is a human gene (UniProt Q68DU8) encoding a BTB/POZ domain protein in the KCTD family. Despite the name, KCTD proteins are not ion channels; they are soluble adaptor or scaffold proteins defined by an N-terminal BTB domain (pmc.ncbi.nlm.nih.gov). KCTD16 is one of four KCTD subunits (along with KCTD8, KCTD12, and KCTD12b) that serve as auxiliary subunits of the GABA_B (γ-aminobutyric acid type B) receptor in the brain (pmc.ncbi.nlm.nih.gov). The GABA_B receptor is a metabotropic G-protein-coupled receptor (GPCR) that mediates slow inhibitory neurotransmission. It consists of principal subunits (GABA_B1 and GABA_B2) forming the core receptor, and auxiliary subunits like KCTD16 which modulate the receptor’s signaling output (pmc.ncbi.nlm.nih.gov). KCTD16’s association with GABA_B receptors is supported by proteomic studies that identified KCTD8/12/16 as stable components of native GABA_B receptor complexes (pmc.ncbi.nlm.nih.gov). In essence, KCTD16 acts as a non-catalytic regulatory protein that fine-tunes GABA_B receptor function, rather than directly performing enzyme or transporter activity. This modulatory role is significant because GABA_B receptor malfunction is linked to neurological and mood disorders (spasticity, epilepsy, addiction, anxiety) (pmc.ncbi.nlm.nih.gov). Understanding KCTD16 is therefore key to understanding how inhibitory synaptic signals are shaped and how their dysregulation might contribute to disease.

Gene and Protein Features: The human KCTD16 gene (also known as KIAA1317) is predominantly expressed in the brain (showing biased brain enrichment in RNA profiling) (www.ncbi.nlm.nih.gov). Its protein product is ~285 amino acids and contains a BTB/POZ domain (also called a T1 domain) at the N-terminus, which mediates protein oligomerization. KCTD16 belongs to the “clade F” subgroup of KCTDs, along with KCTD8 and KCTD12, which share sequence homology in their C-termini (pmc.ncbi.nlm.nih.gov). Notably, unlike many BTB-domain proteins that function as Cullin-3 ubiquitin ligase adaptors, KCTD16 does not bind to the Cul3 scaffold and is not known to participate in ubiquitin E3 ligase complexes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Instead, its BTB domain primarily mediates assembly into a higher-order complex. Biophysical studies have revealed that the BTB domain of KCTD16 forms an oligomeric structure (a pentamer) with a distinctive “open” pentameric conformation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Within GABA_B receptor complexes, KCTD16 and related subunits can attach as homo-pentamers or even form hetero-oligomers (mixing different KCTD types), wrapping around the cytosolic tail of the GABA_B2 subunit (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This unique pentameric assembly is a hallmark of the KCTD family’s interaction with receptors and contrasts with the dimeric assemblies of BTB domains in typical Cullin3-adaptor proteins.

Structure and Domain Organization

BTB/POZ Domain: The N-terminal BTB domain (∼130 amino acids) of KCTD16 is responsible for both KCTD16’s self-oligomerization and its docking to the GABA_B2 receptor. A high-resolution crystal structure (2019) of the human KCTD16 BTB domain bound to a GABA_B2 tail peptide (residues 895–909) revealed how five KCTD16 subunits form a pentameric ring encircling the receptor’s cytoplasmic tail (pmc.ncbi.nlm.nih.gov). Point mutations in this interface (e.g. KCTD16 Phe80→Ala in the BTB domain) abolish binding to GABA_B2, confirming that the BTB domain is the contact site for the receptor (pmc.ncbi.nlm.nih.gov). The BTB domain also underlies the ability of different KCTDs to form mixed complexes. Studies have shown KCTD16 can form hetero-pentamers with KCTD12 or KCTD8 when co-expressed, producing intermediate functional properties (pmc.ncbi.nlm.nih.gov). This suggests the BTB domains of clade F KCTDs are compatible enough to co-assemble, diversifying the potential regulatory outcomes at GABA_B receptors. Notably, the KCTD16 BTB domain adopts an “open” pentamer conformation (a somewhat expanded pentamer) as opposed to the more symmetric closed pentamers seen in some other KCTDs (pmc.ncbi.nlm.nih.gov). This open architecture may relate to its inability to bind Cul3 (pmc.ncbi.nlm.nih.gov) and possibly to how it accommodates the receptor tail. Indeed, a comparative structural analysis in 2017 found that KCTD16 (and the related KCTD1) form unusual pentamers and do not interact with Cul3, whereas other KCTDs form tighter oligomers that readily bind Cul3 (pmc.ncbi.nlm.nih.gov).

C-terminal Domains (H1 and H2): Beyond the BTB domain, KCTD16 contains two conserved C-terminal regions, historically termed the H1 and H2 domains (homology domains 1 and 2) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These domains are crucial for KCTD16’s regulatory function. The H1 domain (present in KCTD8, 12, and 16) mediates interactions with G-protein beta-gamma subunits (Gβγ) and is directly responsible for altering GABA_B signaling kinetics (pmc.ncbi.nlm.nih.gov). In contrast, the H2 domain exists in KCTD8 and KCTD16 but is absent in KCTD12, and it serves an autoinhibitory role: the H2 region of KCTD16 can fold back onto its H1 domain to modulate or restrain its activity (pmc.ncbi.nlm.nih.gov). Functional assays demonstrated that the H1 domain of KCTD12 alone is sufficient to induce rapid desensitization of GABA_B responses, whereas KCTD16’s H2 domain counteracts such an effect in KCTD16 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In other words, KCTD16’s H2 segment prevents the H1 segment from over-sequestering the G-protein, thereby suppressing rapid desensitization that would otherwise occur. A 2012 biochemical study provided evidence for this: swapping or mutating these domains showed that only KCTD8 and KCTD16 (which have H2) generated sustained, non-desensitizing currents, whereas KCTD12 (lacking H2) caused pronounced desensitization (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This domain organization (BTB–H1–H2) defines KCTD16’s function as a modulator that can both accelerate and limit receptor signaling, as discussed below.

Role in GABA_B Receptor Function

Auxiliary Subunit Function: KCTD16 is an integral auxiliary component of the GABA_B receptor signaling complex. GABA_B receptors are obligatory heterodimers (GABA_B1 binds the neurotransmitter GABA, and GABA_B2 couples to G-proteins) that signal via Gi/Go proteins to regulate downstream effectors like ion channels (pmc.ncbi.nlm.nih.gov). When KCTD16 associates with the GABA_B2 subunit’s intracellular tail, it does not affect GABA binding directly, but it profoundly influences the receptor’s signaling kinetics and pharmacology (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Specifically, KCTD16 (as well as KCTD8 and KCTD12) determines how quickly and for how long the GABA_B receptor can activate G-protein gated inward-rectifier K^+ channels (GIRKs) and inhibit Ca^2+ channels on neurons. Experimental studies comparing receptor responses have shown that:

• Faster Onset: The presence of KCTD subunits speeds up the onset of GABA_B-mediated currents. All three auxiliary subunits (8, 12, 16) were found to increase the activation rate of GIRK currents following GABA_B stimulation, compared to receptors without KCTDs (pmc.ncbi.nlm.nih.gov). This is attributed to a “pre-assembled” signaling complex: KCTD16 tethers parts of the G-protein in close proximity to the receptor and effector channel, so that when GABA binds, the channel opens more rapidly. A recent study (Biochem. Pharmacol. 2024) confirmed that KCTD proteins can preassemble specific Gβγ subunits with the GABA_B receptor, markedly accelerating GIRK channel gating upon receptor activation (pmc.ncbi.nlm.nih.gov). In practical terms, neurons expressing KCTD16 exhibit a quicker inhibitory postsynaptic potential in response to GABA, enhancing the timing precision of synaptic inhibition.

• Desensitization and Persistence: While KCTD12 causes the GABA_B response to desensitize rapidly (fade away even in continued presence of agonist), KCTD16 has the opposite effect – it largely prevents rapid desensitization, allowing a more sustained response (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Electrophysiological studies in heterologous cells have demonstrated this stark difference. In cells expressing GABA_B plus KCTD12, GABA-triggered K^+ currents peak and then quickly diminish (due to KCTD12 uncoupling the G-protein), whereas with KCTD16, the induced currents remain near peak as long as GABA is present (pmc.ncbi.nlm.nih.gov). KCTD16’s H2 domain is responsible for this sustained signaling – it blocks the desensitizing action that the H1 domain would otherwise exert (pmc.ncbi.nlm.nih.gov). Therefore, KCTD16-containing GABA_B receptors produce more persistent inhibitory signals. This has been observed in vitro and is supported by chimeric domain-swap experiments: inserting the H2 domain of KCTD16 into KCTD12 can convert KCTD12 into a non-desensitizing variant (pmc.ncbi.nlm.nih.gov). In summary, KCTD16 acts as a brake on desensitization, promoting longer-lasting GABA_B receptor activity.

• Pharmacological Modulation: By altering kinetics, KCTD16 also subtly changes the pharmacological profile of GABA_B receptors. For example, receptors with different KCTD subunits can show different sensitivities to agonists or differences in how quickly they shut off after agonist removal (pmc.ncbi.nlm.nih.gov). A 2017 study found that hetero-oligomers of KCTD12/16 confer unique kinetic and pharmacological properties not seen with either subunit alone (pmc.ncbi.nlm.nih.gov). KCTD16 might also influence the efficacy of allosteric modulators or the extent of GABA_B’s effect on second messengers (like cAMP), although this is an area of ongoing research. It’s worth noting that GABA_B receptors are clinical drug targets (e.g. baclofen is a GABA_B agonist for spasticity), and thus understanding KCTD16’s effect has therapeutic implications. If KCTD16 makes receptor signaling more sustained, drugs that enhance KCTD16 expression or function could potentially prolong GABA_B signaling in disorders where it is beneficial (conversely, dampening KCTD12’s effect might prevent excessive desensitization in chronic treatment settings) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Mechanistic Basis – G-protein Interaction: KCTD16 modulates receptor signaling by directly interacting with the G-protein subunits released upon receptor activation. Normally, when GABA_B is stimulated, the Gα_o/i subunit inhibits adenylate cyclase and the Gβγ dimer opens GIRK channels and inhibits Ca^2+ channels. KCTD16, tethered to GABA_B2, interacts with the Gβγ dimer via its H1 domain (pmc.ncbi.nlm.nih.gov). Biochemical and biophysical experiments have shown that KCTD16 can bind Gβγ even before receptor activation, effectively sequestering Gβγ near the receptor at rest (pmc.ncbi.nlm.nih.gov). In a 2023 study using bioluminescence resonance energy transfer (BRET), KCTD16 exhibited a high basal association with Gβγ and only a modest further change after receptor stimulation, indicating that KCTD16-Gβγ complexes exist prior to agonist binding (pmc.ncbi.nlm.nih.gov). This pre-association explains the accelerated channel activation: the Gβγ is already “in position” to gate the K^+ channel once GABA triggers Gα subunit dissociation. However, unlike KCTD12, KCTD16’s grip on Gβγ is self-limited by the H2 domain. Structural insights highlight this difference: a 2019 cryo-EM structure of KCTD12’s H1 domain bound to Gβ_1γ_2 showed a pentameric H1 “tentacle” surrounded by five Gβγ dimers (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). KCTD12 effectively cages multiple Gβγ subunits, pulling them away from the membrane which causes rapid channel closure (desensitization) (pmc.ncbi.nlm.nih.gov). KCTD16’s H2 domain likely prevents such a tight Gβγ binding configuration, so Gβγ remains available to continue signaling. In line with this model, in vitro assays demonstrated that mutating KCTD16’s H2 domain leads to enhanced desensitization, behaving more like KCTD12 (pmc.ncbi.nlm.nih.gov). Figurely, one can imagine the KCTD16 pentamer dangling from the receptor tail: upon GABA binding, KCTD16 helps push the Gα subunit off (facilitating Gβγ activation of GIRK), but then refrains from clamping onto Gβγ, allowing the channel to stay open (pmc.ncbi.nlm.nih.gov). This model – where KCTD12 is an “off-switch” and KCTD16 a “sustain-switch” for GABA_B signaling – is supported by multiple lines of evidence including co-immunoprecipitation (showing KCTD16 robustly pulls down Gβγ in cell extracts) (pmc.ncbi.nlm.nih.gov) and electrophysiology in neurons (pmc.ncbi.nlm.nih.gov).

Biological Processes and Localization

Cellular and Tissue Localization: KCTD16 is primarily a neuronal protein. It is expressed throughout the central nervous system, with mRNA and protein found in many brain regions (Human Protein Atlas data indicate highest expression in brain, with very low levels in peripheral tissues) (www.ncbi.nlm.nih.gov). Within neurons, KCTD16 is localized to the cytoplasmic side of the plasma membrane wherever GABA_B receptors reside. GABA_B receptors are present both post-synaptically (on dendrites of neurons, mediating slow inhibitory postsynaptic currents) and pre-synaptically (on nerve terminals, modulating neurotransmitter release) (pmc.ncbi.nlm.nih.gov). Auxillary subunits like KCTD16 have been identified in both contexts. For instance, one study noted that KCTD16 (and KCTD8/12) are present in excitatory as well as inhibitory neurons, indicating a broad role in tuning synaptic transmission across different circuit types (pmc.ncbi.nlm.nih.gov). KCTD16 lacks any transmembrane region; it is peripherally attached to membranes via protein–protein interactions. Specifically, KCTD16 co-assembles with GABA_B2 subunits in the endoplasmic reticulum and Golgi during receptor trafficking, and this complex trafficks to the cell surface as a unit (pmc.ncbi.nlm.nih.gov). Evidence for this comes from co-expression experiments where KCTD subunits were required for efficient surface expression of GABA_B in certain neurons (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Moreover, imaging of tagged KCTD16 has shown a punctate distribution in neurites consistent with clustering at GABA_B receptor sites (e.g. in dendritic spines or axon terminals where GABA_B receptors concentrate).

Functionally, KCTD16 operates at the interface of the receptor and intracellular signaling pathways, making it part of the inhibitory signaling microdomain. By shaping GABA_B receptor signaling, KCTD16 indirectly influences downstream processes such as neuronal excitability, synaptic plasticity, and network oscillations. For example, a GABA_B receptor on a presynaptic terminal can inhibit neurotransmitter release via Gβγ-mediated inhibition of voltage-gated Ca^2+ channels. If that receptor complex contains KCTD16, the inhibition might set in quickly and last longer during a burst of GABA, compared to another synapse with KCTD12 where inhibition would fade more quickly. Similarly, postsynaptically, KCTD16-containing receptors mediate longer GIRK channel openings, affecting the duration of slow inhibitory postsynaptic potentials. These differences can translate into measurable effects on behavior and physiology, as described below.

Biological Processes and Pathways: KCTD16 is chiefly involved in the GABAergic inhibitory pathway. It plays a role in:
- Regulation of postsynaptic membrane potential: By controlling GIRK channel activity through GABA_B, KCTD16 helps regulate the postsynaptic excitability of neurons (www.ncbi.nlm.nih.gov). In GO annotations, KCTD16 has been linked to GPCR signaling involved in postsynaptic membrane potential regulation, which reflects its modulatory effect on ion channel coupling.
- Regulation of presynaptic transmitter release: Via presynaptic GABA_B receptors, KCTD16 can influence neurotransmitter release (GABA_B activation on axon terminals inhibits Ca^2+ influx and transmitter release). KCTD16’s presence may prolong this inhibition, thus affecting synaptic transmission dynamics during repetitive activity (www.ncbi.nlm.nih.gov). A recent study in 2021 found that auxiliary KCTD subunits modulate GABA_B-receptor-mediated suppression of neurotransmitter release from specific neurons (e.g. habenula terminals) (pmc.ncbi.nlm.nih.gov). Although that study focused on KCTD8/12, it underscores the pathway KCTD16 participates in: GABA_B to Gβγ to Ca^2+ channel inhibition in terminals.
- Second messenger regulation: Through Gα_o, GABA_B receptors inhibit adenylate cyclase and reduce cAMP levels. KCTD16 may indirectly modulate this Gα-mediated pathway. Interestingly, a 2023 analysis reported that many KCTDs, possibly including KCTD16, can dampen Gβγ-dependent sensitization of adenylyl cyclase (a feedback phenomenon) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In striatal neurons, overexpression of certain KCTDs blunted the increase in cAMP that normally follows prolonged Gi signaling, presumably by sequestering Gβγ. While that study highlighted KCTD2/5/17, the shared capacity of KCTD16 to bind Gβγ suggests it might have a similar influence on cAMP regulation under specific conditions. This places KCTD16 in the context of broader GPCR signaling beyond just ion channel regulation.

Overall, KCTD16’s activity is tightly connected to the GABA_B-G protein-GIRK/Ca^2+ channel signaling axis. By controlling the timing and duration of this inhibitory signaling, KCTD16 contributes to processes like fear memory, mood regulation, and seizure susceptibility. Indeed, GABA_B receptors are known to modulate network excitability and synaptic plasticity, and KCTD16 fine-tunes these effects, as evidenced by phenotypes in mice (next section) and associations with psychiatric conditions.

Experimental Insights and Phenotypes

Knockout Mouse Phenotypes: Genetic studies provide insight into KCTD16’s function in vivo. Kctd16 knockout mice have been generated and analyzed for behavioral and physiological changes. Notably, mice lacking KCTD16 exhibit altered fear memory processing (pmc.ncbi.nlm.nih.gov). In one study, Kctd16^-/- mice demonstrated abnormalities in fear learning paradigms (e.g. auditory cued fear conditioning) compared to wild-type mice (pubmed.ncbi.nlm.nih.gov). While the detailed results showed some differences distinct from Kctd12^-/- mice, both knockouts point to KCTD subunits affecting emotional memory circuits. Specifically, Kctd16 knockout mice displayed changes in fear extinction and recall, suggesting that prolonged inhibitory signaling via GABA_B (which would normally be supported by KCTD16) is important for normal fear memory consolidation and extinction (pmc.ncbi.nlm.nih.gov). These behavioral “endophenotypes” link KCTD16 to the neural circuitry of the amygdala and hippocampus, where fear memories are encoded. Supporting this, in vitro electrophysiology in hippocampal slices from Kctd16^-/- mice showed modified GABA_B-receptor-mediated currents, consistent with the loss of the sustained component normally conferred by KCTD16 (the currents in knockouts desensitized more quickly) (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

This phenotype parallels findings in Kctd12 knockout mice, which have increased anxiety-like behavior and enhanced cued fear learning (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The fact that removing either KCTD16 or KCTD12 impacts fear and anxiety behaviors underscores the importance of properly timed GABA_B inhibition in regulating emotion. It has been proposed that KCTD16 might be more relevant in certain brain regions or developmental periods – for instance, KCTD16 mRNA is enriched in the forebrain (cortex, hippocampus) during development, hinting it could shape the maturation of synaptic inhibition and plasticity. More research is needed, but the available evidence firmly places KCTD16 in the context of neuropsychiatric-relevant phenotypes. As one expert review noted, disruption of KCTD8/12/16 could contribute to “related conditions” given GABA_B’s implication in disorders like epilepsy, depression, and schizophrenia (pmc.ncbi.nlm.nih.gov). No gross developmental abnormalities were reported in Kctd16 knockout mice, suggesting KCTD16’s role is more in neural communication than in brain morphogenesis.

Disease Associations: While no single-gene Mendelian disorders are linked to KCTD16, there are hints from human genetics and clinical studies that KCTD16 may be involved in neuropsychiatric conditions. The KCTD16 gene lies on chromosome 5q31.3; this region has not been as prominently highlighted in genome-wide association studies as the 16p11.2 locus containing KCTD13, for example. However, because KCTD16 modulates GABA_B receptors – and GABA_B dysfunction has been associated with mood disorders, addiction, and epilepsy – researchers have posited that KCTD16 variants could influence disease risk. A 2019 review pointed out that elevated KCTD12 protein levels were observed in brains of patients with depression and schizophrenia, linking GABA_B receptor modulators to those illnesses (pmc.ncbi.nlm.nih.gov). By analogy, changes in KCTD16 expression or function might also affect mood regulation. Indeed, both KCTD12 and KCTD16 are mentioned as potentially contributing to neuropsychiatric phenotypes (with KCTD12 more firmly tied via human data, and KCTD16 via animal data) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). So far, direct genetic associations for KCTD16 are limited, but one study did find that KCTD16 was among genes with altered expression in stress-related mouse models (though changes in KCTD16 have not been confirmed in human patient tissues).

On a different front, autoimmune neurological disease has unexpectedly highlighted KCTD16’s clinical relevance. In 2019, an examination of patients with anti-GABA_B receptor encephalitis (a rare autoimmune disorder causing seizures and limbic encephalitis) discovered that many patients also had antibodies against KCTD16 (academic.oup.com). Specifically, KCTD16 autoantibodies were detected in 23 of 32 (72%) patients with anti-GABA_BR encephalitis, whereas none of 329 control subjects had such antibodies (academic.oup.com). The presence of anti-KCTD16 antibodies correlated strongly with a paraneoplastic origin of the encephalitis: 95% of patients with KCTD16 antibodies had an underlying tumor (often small-cell lung carcinoma, SCLC), compared to 33% of those without KCTD16 antibodies (academic.oup.com). In other words, KCTD16 has become recognized as a marker of cancer-associated GABA_B autoimmunity. This finding makes sense because certain tumors (like SCLC) aberrantly express neuronal proteins such as GABA_B receptors and KCTD16, triggering an immune response. Clinically, this is important – including KCTD16 in diagnostic cell-based assays for GABA_B receptor antibodies improved the sensitivity of detecting this encephalitis, without loss of specificity (academic.oup.com). Moreover, patients with KCTD16 antibodies tended to have more severe disease (higher antibody titers in cerebrospinal fluid and more frequent seizures/status epilepticus) (academic.oup.com) (academic.oup.com). Thus, KCTD16 is now implicated in a real-world medical context: it is a target of autoantibodies causing neurological illness, and it hints at the need to survey for cancer when such antibodies are found. This discovery underscores that KCTD16 is not only functionally important for neurons but also sufficiently antigenic and unique to serve as an immune target.

Beyond the nervous system, KCTD16 has not been widely linked to other organ systems. However, some large-scale studies have started to evaluate KCTD gene family expression in cancers. In a 2025 analysis of ovarian cancer, members of the KCTD family were found to have dysregulated expression, including KCTD16 being significantly upregulated in ovarian tumor tissues relative to normal tissues (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The same study reported that high KCTD16 expression was associated with worse patient prognosis (for instance, patients with elevated KCTD16 had a hazard ratio ~1.28 for poorer survival, p = 0.029) (pmc.ncbi.nlm.nih.gov). While KCTD16’s role in tumors is not understood (it may be incidental or related to altered cell signaling in cancer cells), such data suggest KCTD16 could be explored as part of a panel of biomarkers. Interestingly, other KCTDs (e.g. KCTD11, an established Cul3 adaptor) have tumor suppressor functions. KCTD16 lacks the Cul3 interaction, so if it influences cancer cell behavior, it might be through modulating GPCR signaling or other protein interactions in the cell. These emerging findings open new questions about whether KCTD16 has unrecognized roles beyond the brain, but neurological function remains its primary context.

Recent Developments (2023–2024) and Expert Perspectives

Research on KCTD16 and its family has accelerated in recent years, with contemporary studies providing deeper mechanistic insight and exploring clinical applications:

• Comprehensive KCTD–G Protein Interactions: In 2023, Sloan et al. (J. Biol. Chem., March 2023) systematically screened all 25 human KCTD family members for their ability to interact with G-protein βγ subunits. They found that nearly all KCTDs can bind Gβγ, suggesting a conserved property of the family (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). KCTD16 was confirmed to bind Gβγ, although it showed an interesting behavior of high constitutive binding (high basal BRET signal) with only a mild change upon receptor activation (pmc.ncbi.nlm.nih.gov). This aligns with earlier notions that KCTD16 preassembles with Gβγ at rest. The study also noted that different KCTDs varied in their efficacy of dampening Gβγ-driven signaling; some (like KCTD2/5/17) strongly blunted Gβγ effects on cAMP production (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). KCTD16 was not highlighted as a major modulator of cAMP in that assay, possibly because in a heterologous system its impact is more specific to the GABA_B context. Nonetheless, the broad takeaway is that KCTD16 is part of a family-wide mechanism of GPCR signal modulation via Gβγ sequestration, expanding our understanding of how widespread this regulatory mode might be. Experts have pointed out that KCTD proteins represent a novel class of GPCR modulators, “well positioned to shape GPCR pharmacology” due to their ability to interface with G proteins (pmc.ncbi.nlm.nih.gov). This has spurred interest in targeting KCTD–Gβγ interactions as a way to fine-tune GPCR signals in disease contexts.

• Structural Mechanisms of Desensitization: Building on structures of KCTD16 and KCTD12, researchers have proposed refined models for how these subunits act as molecular timers for receptor signaling. A 2017 Nature study (Fritzius et al., 2017) described KCTD12 as an “off-switch” that induces rapid desensitization by capturing Gβγ (pmc.ncbi.nlm.nih.gov). In contrast, KCTD16 (and KCTD8) were described as having an “auto-inhibited state” that prevents them from immediately binding Gβγ, thus delaying or preventing desensitization (pmc.ncbi.nlm.nih.gov). The 2019 PNAS study by Zuo et al. provided the first crystal structure of a KCTD16 oligomer with a GABA_B2 fragment, solidifying the concept that the receptor’s tail threads into the center of a KCTD pentamer (pmc.ncbi.nlm.nih.gov). Qing Fan, one of the senior authors, highlighted that this structure “sheds light on the assembly of the GABA_B receptor signaling complex” and reveals a clear binding interface that could be targeted to disrupt or enhance KCTD16-receptor interaction (pmc.ncbi.nlm.nih.gov). Knowing this interface at atomic detail opens the door for drug design – for instance, small molecules that stabilize KCTD16 on the receptor might prolong GABA_B signaling, which could be useful in certain neurological disorders. Conversely, molecules that block KCTD12 binding might prevent excessive desensitization and enhance GABA_B responses in conditions like depression (where GABA_B function may be deficient). Such therapeutic speculation is in early stages, but it stems directly from these structural and mechanistic insights.

• Autoantibody Diagnostics: As discussed, the recognition of KCTD16 as an autoantigen in GABA_B receptor encephalitis (first reported in Brain, June 2019) is now shaping clinical practice. Neurologists now test for anti-KCTD16 antibodies in patients with unexplained seizures and encephalitic presentations. The 2019 study by de Bruijn et al. demonstrated that adding KCTD16 to cell-based antibody assays increased detection sensitivity from about 59% (with only GABA_B1/B2 in the assay) to ~84% when KCTD16 was included (academic.oup.com). Since most of these KCTD16-positive cases are paraneoplastic, this lab finding directly guides oncological investigations (e.g. screening for a hidden small-cell lung cancer in a patient with limbic encephalitis) (academic.oup.com) (academic.oup.com). It’s a prime example of a basic science discovery (KCTD16’s role in the receptor) translating into a real-world diagnostic tool within a short time. Furthermore, it provides a biological rationale for the severe seizures observed in these patients: antibodies might be disrupting KCTD16 function, thereby altering GABA_B receptor kinetics and making neuronal inhibition less sustained, potentially promoting hyperexcitability.

• Cancer Genomics: While KCTD16 is not a well-known oncogene or tumor suppressor, the 2025 Cancer Medicine study (Zhang et al., 2025) exemplifies a growing research trend of surveying “hidden” gene families in cancer. This study found KCTD16 mRNA was up-regulated in ovarian cancer cell lines and tumors, alongside KCTD5, KCTD9, and KCTD12, whereas some other KCTDs were down-regulated (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The authors performed ROC analysis and found KCTD16 had a moderate diagnostic value (AUC ~0.8) for distinguishing ovarian cancer tissue from normal (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Although KCTD16’s function in ovarian cancer is unclear, one hypothesis is that changes in GPCR signaling pathways in tumors (many ovarian cancers have aberrant GPCR and G-protein activity) might select for altered expression of GPCR modulators like KCTDs. Additionally, KCTD16 has a CpG island in its promoter, and the 2025 study noted that DNA methylation changes in several KCTD genes correlated inversely with their expression in cancer (pmc.ncbi.nlm.nih.gov). For KCTD16 specifically, hypomethylation might explain its over-expression in tumors. Importantly, this research is still early and primarily descriptive. Experts caution that high expression of KCTD16 could either be a passenger effect or potentially influence cell signaling to confer growth advantages. Regardless, such findings expand the relevance of KCTD16 beyond the brain, suggesting it may be involved in cellular pathways that, when dysregulated, contribute to diseases like cancer.

Expert Commentary: Scientific interest in KCTD16 mirrors the broader interest in KCTD proteins as modulators of key signaling pathways. A 2019 review by Teng et al. in CNS Neuroscience & Therapeutics argued that the “poorly characterized human KCTD gene family” deserves deeper investigation due to emerging evidence linking various KCTDs to neurological disorders (pmc.ncbi.nlm.nih.gov). The authors highlighted KCTD12’s ties to bipolar disorder and KCTD13’s involvement in neurodevelopmental disorders, while noting that KCTD16, KCTD8, and KCTD12 form a functionally related subgroup influencing neurotransmitter receptor signaling (pmc.ncbi.nlm.nih.gov). They described recent structural studies (citing work on KCTD12 and KCTD16) as providing “mechanisms of regulating membrane channel activities through modulation of distinct GTPases” (pmc.ncbi.nlm.nih.gov) – essentially pointing out that KCTDs regulate ion channels by interfacing with G-proteins (a novel mechanism for protein regulation). In the same review, the model of KCTD12/16 action on GIRK channels is summarized, emphasizing how KCTD12’s sequestration of Gβγ accelerates channel deactivation, whereas KCTD16’s H2 domain prevents this sequestration (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The review underscores that while KCTD12 has been more extensively studied (due to psychiatric genetic links), KCTD16 likely plays complementary roles and could be implicated in “related conditions” especially where GABA_B signaling is a factor (pmc.ncbi.nlm.nih.gov).

Another expert perspective can be found in a 2022 commentary on G protein-gated K^+ channels (Luo et al., 2022, Am J Physiol Cell Physiol). The authors note that the discovery of KCTD auxiliary subunits has “significantly expanded our understanding of GABA_B receptor function,” allowing the receptor’s inhibitory signals to be “tuned by cell-specific expression of KCTD8, 12, or 16” (since different neurons express different ratios of these subunits) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). They further mention that targeting these subunits could yield new pharmacological avenues – for instance, a molecule that enhances KCTD16’s interaction with GABA_B2 might prolong GABA_B-mediated inhibition therapeutically. While such drugs are hypothetical at present, the concept reflects a growing recognition of auxiliary proteins like KCTD16 as drug targets themselves or as part of receptor complexes to target.

In summary, current expert consensus portrays KCTD16 as a critical modulatory subunit that defines the timing of inhibitory GABA_B signals. It is part of a mechanism nature uses to diversify GPCR signaling outcomes, and its dysfunction or removal can have notable neural consequences. The most recent research (2023–2024) has reinforced KCTD16’s role in Gβγ management and highlighted its relevance in contexts ranging from autoimmune encephalitis diagnostics to cancer biomarker studies. As one paper succinctly stated, KCTD subunits like 16 “induce desensitization of K^+ currents in response to GABA_B activation in a subtype-specific manner” (academic.oup.com) – a reminder that each KCTD subtype (8, 12, 16) confers unique properties. Going forward, investigating KCTD16 in specific neuron types and disease models (e.g. stress, epilepsy, or mood disorder models) will be important to fully elucidate its functions. With structural biology providing detailed interaction maps, and clinical findings giving real-world significance, KCTD16 has moved from an obscure KIAA gene to a protein of substantial interest in neuroscience and beyond.

References: (Publication dates and sources are included in citation brackets)

Citations

1. AnnotationURLCitation(end_index=515, start_index=333, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=domains%20embedded%20in%20potassium%20channels,little%20involvement%20in%20potassium%20channeling')
2. AnnotationURLCitation(end_index=865, start_index=691, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=Mouse%20Kctd8%2C%20Kctd12%2C%20Kctd12b%20,Therefore%2C%20disruption%20of%20the%20auxiliary')
3. AnnotationURLCitation(end_index=1327, start_index=1153, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=Malfunction%20of%20the%20receptor%20is,to%20neurotransmitters%2C%20while%20the%20auxiliary')
4. AnnotationURLCitation(end_index=1655, start_index=1491, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
5. AnnotationURLCitation(end_index=2159, start_index=1985, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=Malfunction%20of%20the%20receptor%20is,to%20neurotransmitters%2C%20while%20the%20auxiliary')
6. AnnotationURLCitation(end_index=2681, start_index=2490, title='KCTD16 potassium channel tetramerization domain containing 16 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=57528#:~:text=Expression%20Biased%20expression%20in%20brain,other%20tissues%20See%20more%20Orthologs')
7. AnnotationURLCitation(end_index=3097, start_index=2967, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=3,in%20neurotransmitter%20receptor%20signaling')
8. AnnotationURLCitation(end_index=3497, start_index=3304, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=domains%20with%20the%20exception%20of,KCTD13%20%28K_%7Bd%7D%E2%80%89%3D%E2%80%89100%E2%80%85nM%29%2C%20KCTD10')
9. AnnotationURLCitation(end_index=3665, start_index=3498, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=Evolutionarily%20distant%20from%20these%20family,here%20that%20this%20geometry%20is')
10. AnnotationURLCitation(end_index=4027, start_index=3909, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=,Cul3%20and%20were%20observed%20to')
11. AnnotationURLCitation(end_index=4221, start_index=4028, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=domains%20with%20the%20exception%20of,KCTD13%20%28K_%7Bd%7D%E2%80%89%3D%E2%80%89100%E2%80%85nM%29%2C%20KCTD10')
12. AnnotationURLCitation(end_index=4597, start_index=4433, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
13. AnnotationURLCitation(end_index=4724, start_index=4598, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=increase%20the%20activation%20rate%20of,19')
14. AnnotationURLCitation(end_index=5474, start_index=5348, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=increase%20the%20activation%20rate%20of,19')
15. AnnotationURLCitation(end_index=5774, start_index=5648, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=increase%20the%20activation%20rate%20of,19')
16. AnnotationURLCitation(end_index=6163, start_index=5999, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
17. AnnotationURLCitation(end_index=6612, start_index=6494, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=,Cul3%20and%20were%20observed%20to')
18. AnnotationURLCitation(end_index=6871, start_index=6678, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=domains%20with%20the%20exception%20of,KCTD13%20%28K_%7Bd%7D%E2%80%89%3D%E2%80%89100%E2%80%85nM%29%2C%20KCTD10')
19. AnnotationURLCitation(end_index=7306, start_index=7139, title='Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5664961/#:~:text=Evolutionarily%20distant%20from%20these%20family,here%20that%20this%20geometry%20is')
20. AnnotationURLCitation(end_index=7619, start_index=7487, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=of%20KCTD12%20and%20KCTD12b%20mediate,20%2C%2023')
21. AnnotationURLCitation(end_index=7786, start_index=7620, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
22. AnnotationURLCitation(end_index=8189, start_index=8023, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
23. AnnotationURLCitation(end_index=8572, start_index=8406, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
24. AnnotationURLCitation(end_index=8937, start_index=8771, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
25. AnnotationURLCitation(end_index=9070, start_index=8938, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=of%20KCTD12%20and%20KCTD12b%20mediate,20%2C%2023')
26. AnnotationURLCitation(end_index=9610, start_index=9497, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
27. AnnotationURLCitation(end_index=9743, start_index=9611, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=of%20KCTD12%20and%20KCTD12b%20mediate,20%2C%2023')
28. AnnotationURLCitation(end_index=10430, start_index=10270, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=further%20advance%20the%20field%20overall,B2%7D%20%28amino%20acid%20residues')
29. AnnotationURLCitation(end_index=10792, start_index=10628, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
30. AnnotationURLCitation(end_index=10934, start_index=10793, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=synaptic%20transmission%20by%20indirectly%20regulating,33')
31. AnnotationURLCitation(end_index=11633, start_index=11492, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=synaptic%20transmission%20by%20indirectly%20regulating,33')
32. AnnotationURLCitation(end_index=12217, start_index=12048, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=channels%20through%20trimeric%20G%E2%80%90proteins,B2%7D%20%28amino%20acid%20residues')
33. AnnotationURLCitation(end_index=12779, start_index=12666, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
34. AnnotationURLCitation(end_index=12888, start_index=12780, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=GABA_,channel%29.%20Then')
35. AnnotationURLCitation(end_index=13322, start_index=13209, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
36. AnnotationURLCitation(end_index=13631, start_index=13465, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
37. AnnotationURLCitation(end_index=14024, start_index=13911, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
38. AnnotationURLCitation(end_index=14596, start_index=14432, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
39. AnnotationURLCitation(end_index=14904, start_index=14740, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
40. AnnotationURLCitation(end_index=15685, start_index=15561, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=studies%2C%20the%20KCTD12%20gene%20has,B')
41. AnnotationURLCitation(end_index=15859, start_index=15686, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=inhibitory%20and%20excitatory%20neurons,mice%20exhibit%20related%20phenotypes%20including')
42. AnnotationURLCitation(end_index=16421, start_index=16258, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=H1%20domain%20that%20is%20exclusive,was%20sufficient%20for%20interaction%20with')
43. AnnotationURLCitation(end_index=16736, start_index=16593, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=KCTD5%2C%20and%20KCTD12%29,In%20addition%2C%20we%20revealed')
44. AnnotationURLCitation(end_index=17133, start_index=16990, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=KCTD5%2C%20and%20KCTD12%29,In%20addition%2C%20we%20revealed')
45. AnnotationURLCitation(end_index=17691, start_index=17560, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=GABA_,together%2C%20the%20proposed%20model%20is')
46. AnnotationURLCitation(end_index=17800, start_index=17692, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=GABA_,channel%29.%20Then')
47. AnnotationURLCitation(end_index=18087, start_index=17939, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=KCTD12%20H1%20bound%20to%20G%CE%B2_,19%20A%20role%20for%20KCTD12')
48. AnnotationURLCitation(end_index=18528, start_index=18362, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
49. AnnotationURLCitation(end_index=18928, start_index=18780, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=KCTD12%20H1%20bound%20to%20G%CE%B2_,19%20A%20role%20for%20KCTD12')
50. AnnotationURLCitation(end_index=19309, start_index=19162, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=match%20at%20L165%20Given%20that,myc%20tag%20to%20the%20carboxy')
51. AnnotationURLCitation(end_index=19456, start_index=19343, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
52. AnnotationURLCitation(end_index=19983, start_index=19792, title='KCTD16 potassium channel tetramerization domain containing 16 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=57528#:~:text=Expression%20Biased%20expression%20in%20brain,other%20tissues%20See%20more%20Orthologs')
53. AnnotationURLCitation(end_index=20475, start_index=20312, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=considered%20auxiliary%20subunits%20of%20the,to%20contribute%20to%20bipolar%20I')
54. AnnotationURLCitation(end_index=20915, start_index=20752, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=considered%20auxiliary%20subunits%20of%20the,to%20contribute%20to%20bipolar%20I')
55. AnnotationURLCitation(end_index=21376, start_index=21212, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
56. AnnotationURLCitation(end_index=21678, start_index=21529, title='KCTD8 and KCTD12 Facilitate Axonal Expression of GABAB Receptors in Habenula Cholinergic Neurons - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8896537/#:~:text=KCTD8%20and%20KCTD12%20Facilitate%20Axonal,5%7D%2C%20Minmin%20Luo')
57. AnnotationURLCitation(end_index=21816, start_index=21679, title='Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27717812/#:~:text=subunit%20KCTD16%20,pathophysiology%20of%20a%20number%20of')
58. AnnotationURLCitation(end_index=23467, start_index=23279, title='KCTD16 potassium channel tetramerization domain containing 16 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=57528#:~:text=Summary%20Predicted%20to%20enable%20G,involved%20in%20regulation%20of%20presynaptic')
59. AnnotationURLCitation(end_index=24173, start_index=23985, title='KCTD16 potassium channel tetramerization domain containing 16 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=57528#:~:text=Summary%20Predicted%20to%20enable%20G,involved%20in%20regulation%20of%20presynaptic')
60. AnnotationURLCitation(end_index=24519, start_index=24355, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
61. AnnotationURLCitation(end_index=25186, start_index=25013, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=examining%20sensitization%20of%20the%20adenylyl,to%20shape%20GPCR%20signal%20transmission')
62. AnnotationURLCitation(end_index=25347, start_index=25187, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=D2R%E2%86%92G%CE%B1i%20signaling,Curiously%2C%20KCTD9%20slightly%20inhibited')
63. AnnotationURLCitation(end_index=26714, start_index=26590, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=studies%2C%20the%20KCTD12%20gene%20has,B')
64. AnnotationURLCitation(end_index=26957, start_index=26866, title='Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27717812/#:~:text=,mice%20show')
65. AnnotationURLCitation(end_index=27497, start_index=27373, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=studies%2C%20the%20KCTD12%20gene%20has,B')
66. AnnotationURLCitation(end_index=28038, start_index=27910, title='Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27717812/#:~:text=determine%20the%20kinetics%20of%20the,mice%20show')
67. AnnotationURLCitation(end_index=28152, start_index=28039, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=%2820%2C%2022%29,In%20genetic')
68. AnnotationURLCitation(end_index=28383, start_index=28292, title='Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/27717812/#:~:text=,mice%20show')
69. AnnotationURLCitation(end_index=28520, start_index=28384, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=disorders,several%20cancers%20not%20discussed%20here')
70. AnnotationURLCitation(end_index=29458, start_index=29285, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=inhibitory%20and%20excitatory%20neurons,mice%20exhibit%20related%20phenotypes%20including')
71. AnnotationURLCitation(end_index=30583, start_index=30430, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=subunits%20KCTD8%2C%20KCTD12%2C%20and%20KCTD16,64%20Consistent%20with')
72. AnnotationURLCitation(end_index=30985, start_index=30855, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=3,in%20neurotransmitter%20receptor%20signaling')
73. AnnotationURLCitation(end_index=31138, start_index=30986, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=KCTD12%20and%20KCTD16,function%20and%2For%20GTPase%20modulated%20ion')
74. AnnotationURLCitation(end_index=31864, start_index=31715, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=and%20cell,that%20were%20screened%20sufficiently%2C%2018%2F19')
75. AnnotationURLCitation(end_index=32183, start_index=32034, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=and%20cell,that%20were%20screened%20sufficiently%2C%2018%2F19')
76. AnnotationURLCitation(end_index=32586, start_index=32453, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=match%20at%20L243%20%2895,Thirteen%20patients')
77. AnnotationURLCitation(end_index=33219, start_index=33049, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=addition%20of%20KCTD16%20to%20the,with%20prominent%2C%20severe%20seizures%2C%20but')
78. AnnotationURLCitation(end_index=33505, start_index=33392, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=%2895,Thirteen%20patients')
79. AnnotationURLCitation(end_index=33687, start_index=33506, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=encephalitis%20patients%20with%20KCTD16%20antibodies,without%20KCTD16%20antibodies%20had%20an')
80. AnnotationURLCitation(end_index=34624, start_index=34454, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=KCTD5%2C%20KCTD12%2C%20and%20KCTD16%20were,genes%2C%20except%20for%20KCTD9%2C%20which')
81. AnnotationURLCitation(end_index=34792, start_index=34625, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=match%20at%20L457%20results%20in,in%20tissue%20samples%2C%20indicating%20potential')
82. AnnotationURLCitation(end_index=35126, start_index=34996, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=match%20at%20L544%20KCTD10%2C%20KCTD12%2C,029')
83. AnnotationURLCitation(end_index=36472, start_index=36300, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=G%20protein%E2%80%93coupled%20receptors%20,a%20live%20cell%20bioluminescence%20resonance')
84. AnnotationURLCitation(end_index=36636, start_index=36473, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=H1%20domain%20that%20is%20exclusive,was%20sufficient%20for%20interaction%20with')
85. AnnotationURLCitation(end_index=36961, start_index=36818, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=KCTD5%2C%20and%20KCTD12%29,In%20addition%2C%20we%20revealed')
86. AnnotationURLCitation(end_index=37375, start_index=37212, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=downstream%20through%20the%20cAMP%20pathway,G%CE%B2%CE%B3%20has%20yet%20to%20be')
87. AnnotationURLCitation(end_index=37536, start_index=37376, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=D2R%E2%86%92G%CE%B1i%20signaling,Curiously%2C%20KCTD9%20slightly%20inhibited')
88. AnnotationURLCitation(end_index=38189, start_index=38097, title='Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9976452/#:~:text=Abstract')
89. AnnotationURLCitation(end_index=38800, start_index=38652, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=KCTD12%20H1%20bound%20to%20G%CE%B2_,19%20A%20role%20for%20KCTD12')
90. AnnotationURLCitation(end_index=39144, start_index=38978, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=H2%20is%20not%20present%20in,from%20the%20inhibited%20trimeric%20G%E2%80%90protein')
91. AnnotationURLCitation(end_index=39487, start_index=39361, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=increase%20the%20activation%20rate%20of,19')
92. AnnotationURLCitation(end_index=39861, start_index=39742, title='Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6486783/#:~:text=Human%20GABA_,B%7D%20receptor%20and')
93. AnnotationURLCitation(end_index=41101, start_index=40931, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=addition%20of%20KCTD16%20to%20the,with%20prominent%2C%20severe%20seizures%2C%20but')
94. AnnotationURLCitation(end_index=41429, start_index=41316, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=%2895,Thirteen%20patients')
95. AnnotationURLCitation(end_index=41575, start_index=41430, title='expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies | Brain | Oxford Academic', type='url_citation', url='https://academic.oup.com/brain/article/142/6/1631/5476117#:~:text=of%20KCTD16%20antibodies%20points%20towards,based%20assay')
96. AnnotationURLCitation(end_index=42555, start_index=42403, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=the%20expression%20levels%20of%20KCTD,for%20each%20KCTD%20gene%20to')
97. AnnotationURLCitation(end_index=42726, start_index=42556, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=KCTD5%2C%20KCTD12%2C%20and%20KCTD16%20were,genes%2C%20except%20for%20KCTD9%2C%20which')
98. AnnotationURLCitation(end_index=43016, start_index=42876, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=match%20at%20L403%20%28Figure%C2%A01B%29,Figure%C2%A01B')
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100. AnnotationURLCitation(end_index=43758, start_index=43582, title='Mechanistic Insights Into the Tumor‐Driving and Diagnostic Roles of KCTD Family Genes in Ovarian Cancer: An Integrated In Silico and In\xa0Vitro Analysis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12365668/#:~:text=KCTD12%2C%20KCTD10%2C%20and%20KCTD16%20show,the%20expression%20and%20promoter%20methylation')
101. AnnotationURLCitation(end_index=44773, start_index=44627, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=focusing%20efforts%20to%20dissect%20their,KCTD11%29%20and%20an')
102. AnnotationURLCitation(end_index=45150, start_index=45020, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=3,in%20neurotransmitter%20receptor%20signaling')
103. AnnotationURLCitation(end_index=45504, start_index=45337, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=and%20structure%E2%80%90based%20studies%20,functions%20may%20be%20disease%20related')
104. AnnotationURLCitation(end_index=46026, start_index=45857, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=channels%20through%20trimeric%20G%E2%80%90proteins,B2%7D%20%28amino%20acid%20residues')
105. AnnotationURLCitation(end_index=46158, start_index=46027, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=GABA_,together%2C%20the%20proposed%20model%20is')
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107. AnnotationURLCitation(end_index=47189, start_index=47025, title='GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/#:~:text=Four%20KCTD%20subunits%2C%20KCTD8%2C%2012%2C,subunits%20are%20composed%20of%20an')
108. AnnotationURLCitation(end_index=47363, start_index=47190, title='KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6566181/#:~:text=inhibitory%20and%20excitatory%20neurons,mice%20exhibit%20related%20phenotypes%20including')
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