Overview of KCTD8 (BTB/POZ Domain-Containing Protein KCTD8) OpenAI o3-deep-research-2025-06-26 114 citations 2025-12-27T16:55:44.922127

Overview of KCTD8 (BTB/POZ Domain-Containing Protein KCTD8)

KCTD8 is a human protein (UniProt Q6ZWB6) belonging to the KCTD family – a group of proteins defined by a “potassium channel tetramerization domain” (BTB/POZ domain) in their N-terminus. The KCTD family name reflects structural similarity to the tetramerization (T1) domain of voltage-gated K^+ channels, but KCTD8 itself is not an ion channel. Instead, it functions as an auxiliary (accessory) subunit of the GABA_B (metabotropic GABA type B) receptor, influencing the receptor’s signaling properties (www.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). KCTD8 is one of four KCTD proteins (KCTD8, KCTD12, KCTD12b, and KCTD16) identified in 2010 as additional subunits that assemble with GABA_B receptor complexes (pmc.ncbi.nlm.nih.gov). These auxiliary subunits do not form the receptor’s ligand-binding core, but they attach to the receptor’s intracellular domain and modulate its function (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Importantly, the gene KCTD8 is expressed predominantly in the brain (with highest mRNA levels in neural tissues) and to a lesser extent in a few other tissues (e.g. thyroid), consistent with its neuro-specific role (www.ncbi.nlm.nih.gov).

Key structural features: KCTD8 is a relatively large cytosolic protein (~473 amino acids) composed of modular domains characteristic of the KCTD family. Its N-terminal BTB/POZ domain (also called a T1 domain) mediates self-oligomerization and direct binding to the GABA_B2 receptor subunit’s intracellular tail (pubmed.ncbi.nlm.nih.gov). This BTB domain enables KCTD8 to form a homotetramer (four subunits) when associated with the receptor (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Downstream of the BTB domain, KCTD8 contains a conserved H1 domain (with a beta-propeller-like fold) and a unique H2 domain at its C-terminus (pubmed.ncbi.nlm.nih.gov). The presence of the H2 domain distinguishes KCTD8 (and its close relative KCTD16) from KCTD12, which lacks H2 (pubmed.ncbi.nlm.nih.gov). These domains have pivotal functional roles: the BTB (T1) domain anchors KCTD8 to the GABA_B receptor (specifically to the GABA_B2 subunit), while the H1 domain mediates interaction with the G-protein βγ subunits that are coupled to the receptor (www.ncbi.nlm.nih.gov). In KCTD12 (which causes rapid signal desensitization), a specific short motif in the H1 region (T/NFLEQ sequence) is responsible for accelerating GABA_B signal termination (pubmed.ncbi.nlm.nih.gov). KCTD8’s H1 domain lacks this desensitizing motif and instead is followed by the H2 region, which appears to sterically counteract desensitization (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). As a result, KCTD8 does not promote fast desensitization of GABA_B receptor signaling (pubmed.ncbi.nlm.nih.gov). This structural difference underlies the distinct regulatory effects of various KCTDs on the receptor, as discussed below.

Role as a GABAB Receptor Auxiliary Subunit

Function in GABA_B signaling: KCTD8 is an integral component of certain native GABA_B receptor complexes, where it acts as a non-enzymatic adaptor/regulatory protein influencing GABA_B signal transduction. GABA_B receptors are dimeric G-protein-coupled receptors (GPCRs) for the inhibitory neurotransmitter GABA, and when activated they engage Gi/o-type heterotrimeric G-proteins. The GABA_B heterodimer consists of principal subunits GABA_B1 (ligand-binding) and GABA_B2 (G-protein coupling); KCTD8 attaches to the intracellular domain of GABA_B2 (pubmed.ncbi.nlm.nih.gov). Once bound, KCTD8 helps determine the kinetics and pharmacological profile of the receptor’s response (www.ncbi.nlm.nih.gov). Notably, KCTD8 confers a largely non-desensitizing response to prolonged GABA stimulation (pubmed.ncbi.nlm.nih.gov). In electrophysiological terms, when KCTD8 is part of the GABA_B receptor complex, the downstream G-protein-activated K^+ current (e.g., GIRK channel current that causes neuronal hyperpolarization) remains sustained during continuous agonist presence, with minimal rundown (pubmed.ncbi.nlm.nih.gov). This contrasts with complexes containing KCTD12, which show rapid and pronounced desensitization (a quick decrease of current despite continued agonist) (pubmed.ncbi.nlm.nih.gov). Empirical studies demonstrated these differences: for example, Schwenk et al. (2010) found that KCTD8- or KCTD16-associated GABA_B receptors produce sustained (non-desensitizing) inhibitory currents, whereas KCTD12 produces strong desensitization of the current (pubmed.ncbi.nlm.nih.gov). The mechanistic basis was later elucidated – KCTD8’s H1 domain can bind G-protein βγ subunits without inducing the rapid disengagement that KCTD12 triggers (www.ncbi.nlm.nih.gov). Furthermore, the extra H2 domain in KCTD8 appears to hinder the desensitizing action that an H1 domain alone might have, effectively acting as a brake on signal termination (pubmed.ncbi.nlm.nih.gov). In experiments swapping domains between KCTD subunits, the H2 region of KCTD8/16 was found to suppress desensitization in a steric, sequence-independent manner (when appended to a desensitizing H1) (pubmed.ncbi.nlm.nih.gov). Thus, KCTD8-containing receptor complexes transmit a more persistent inhibitory signal, which may be important for certain physiological contexts requiring sustained GABA_B activity.

Auxiliary subunit assembly and signaling: KCTD8 (like other KCTDs in this family) functions as a tetramer bound to the cytosolic tail of the GABA_B receptor. Cryo-EM and biochemical analyses indicate one GABA_B heterodimer can associate with a homotetramer of KCTD subunits (pubmed.ncbi.nlm.nih.gov). Within this complex, KCTD8 not only contacts the receptor but also is positioned to interact with the G-protein. Indeed, biophysical studies using energy transfer assays showed that KCTD subunits bind both the GABA_B receptor and the G-protein simultaneously (pmc.ncbi.nlm.nih.gov). KCTD8’s interaction with the G-protein βγ subunits likely modulates the coupling efficiency to downstream effectors (such as GIRK K^+ channels or neuronal Ca^2+ channels). One model is that KCTD8 acts as a molecular scaffold that pre-associates with G_βγ, keeping it available at the receptor for sustained signaling, whereas KCTD12 acts more like a sink or modulator that promotes G_βγ re-sequestration (hastening signal termination) (www.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Supporting this, structural data from related KCTDs show the H1 domain directly contacts G_βγ (www.ncbi.nlm.nih.gov). Functionally, the presence of KCTD8 has little effect on the initial activation of GABA_B signaling (onset of the K^+ current) but significantly affects the duration and termination of the response (pubmed.ncbi.nlm.nih.gov). KCTD8-associated signals decay slowly (non-desensitizing), whereas KCTD12-associated signals decay rapidly; KCTD16 (the other H2-containing subunit) produces an intermediate-sustained profile (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). These auxiliary subunits thus create distinct receptor subtypes with different signaling kinetics (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). It’s important to note that KCTD8 itself is not an enzyme or channel – it does not catalyze reactions or directly conduct ions. Instead, its primary function is regulatory and scaffolding, fine-tuning the GABA_B receptor’s communication with intracellular signaling pathways (G-proteins and ion channels).

Expression Pattern and Cellular Localization

Tissue and cellular expression: Consistent with its role in synaptic signaling, KCTD8 is predominantly expressed in the central nervous system. In mice, Kctd8 mRNA is enriched in specific brain regions and neuron populations, with a more restricted expression pattern compared to the broadly expressed KCTD12 and KCTD16 (pubmed.ncbi.nlm.nih.gov). In situ hybridization mapping of the mouse brain showed that KCTD12 and KCTD16 transcripts are widespread, whereas KCTD8 (and the related KCTD12b) are confined to more limited regions or subsets of neurons (pubmed.ncbi.nlm.nih.gov). For example, certain cerebellar neurons or habenular neurons preferentially express KCTD8 or KCTD12, but not both, suggesting cell-type specificity in auxiliary subunit usage (pubmed.ncbi.nlm.nih.gov). Many neurons co-express at least one KCTD family member: most neurons in the brain have some KCTD expression, implying that the majority of native GABA_B receptors incorporate an auxiliary subunit (pubmed.ncbi.nlm.nih.gov). However, the exact KCTD isoform can vary by brain region and developmental stage (pubmed.ncbi.nlm.nih.gov). In the adult rodent hippocampus, for instance, principal cells co-express KCTD12 and KCTD16 (which can form heteromeric complexes; see below), whereas in the cerebellum certain neurons might express only KCTD8 or only KCTD16 at a time (pubmed.ncbi.nlm.nih.gov). Human expression data also indicate KCTD8 is brain-biased, with lower expression in peripheral tissues (a notable exception being the thyroid gland, where moderate KCTD8 expression is reported, though the functional significance there is unclear) (www.ncbi.nlm.nih.gov).

Subcellular localization: As a soluble intracellular protein that binds membrane receptors, KCTD8 is found at the cytoplasmic face of the plasma membrane in cells where it partners with GABA_B receptors. It has no transmembrane region of its own, but co-localizes with GABA_B receptors at synaptic sites. Interestingly, different KCTD family members show distinct subcellular targeting within neurons – some concentrate at dendritic postsynaptic sites, others in axonal or presynaptic compartments (pubmed.ncbi.nlm.nih.gov). KCTD8 appears to have a propensity for axonal/presynaptic localization in certain neurons. A recent study of habenula–interpeduncular pathway neurons (a circuit involved in aversive memory) found that KCTD8 (along with KCTD12) is crucial for enriching GABA_B receptors in axon terminals of those neurons (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In that context, KCTD8 helps traffic or stabilize GABA_B receptors at presynaptic release sites. When KCTD8 and KCTD12 were genetically knocked out in mice, GABA_B receptors were significantly reduced at the axon terminals (but not in the neuron cell bodies), indicating these subunits facilitate receptor transport or retention in axons (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Correspondingly, the absence of KCTD8/12 greatly dampened GABA_B-mediated presynaptic effects – specifically, the normal GABA_B-dependent enhancement of glutamate release (an atypical excitatory action of GABA_B in the habenula circuit) was lost in KCTD8/12 knockouts (pmc.ncbi.nlm.nih.gov). Overexpressing KCTD8 in the knockout neurons could restore GABA_B levels at terminals and rescue the functional effect (pmc.ncbi.nlm.nih.gov). These results suggest KCTD8 not only modulates GABA_B signaling kinetics but also can influence receptor localization and presynaptic signaling strength in certain pathways. In general, KCTD8 is thought to localize wherever its bound GABA_B2 receptor localizes – this can include postsynaptic densities (on dendritic membranes responding to GABA release) or presynaptic membranes (when GABA_B acts as an autoreceptor/modulator on axon terminals). The exact distribution of KCTD8 between pre- vs. postsynaptic compartments likely varies by neuron type. Immunohistochemical studies support that different KCTDs can show distinct axonal or dendritic enrichment in vivo (pubmed.ncbi.nlm.nih.gov), which aligns with the specialized roles (e.g., KCTD8 in presynaptic regulation as seen in habenular neurons).

Oligomerization and Functional Diversity

One important aspect of KCTD8 and its relatives is their ability to form hetero-oligomeric complexes. While KCTD8 typically forms homotetramers, it can also co-assemble with other KCTD subunits if they are co-expressed in the same cell. Research has shown that different KCTD family members can mix, creating heteromeric tetramers with varied subunit composition (pmc.ncbi.nlm.nih.gov). For example, in hippocampal neurons that express both KCTD12 and KCTD16, a significant fraction of KCTD subunits are assembled as KCTD12–KCTD16 heteromers rather than exclusively homomers (pmc.ncbi.nlm.nih.gov). Although KCTD8 was not as widely distributed in those hippocampal cells, it is closely related to KCTD16 and can potentially hetero-oligomerize with KCTD16 or KCTD12 when co-expressed (www.mdpi.com) (www.mdpi.com). In vitro co-immunoprecipitation and bioluminescence energy transfer experiments have confirmed that KCTD8 can interact and form complexes with KCTD16 (and to some extent with other KCTDs) (www.mdpi.com) (www.mdpi.com). On the other hand, some pairings are unfavorable (e.g., KCTD8 did not strongly co-assemble with KCTD5’s BTB domain alone, indicating the C-terminal regions mediate certain specific interactions) (www.mdpi.com) (www.mdpi.com). The functional consequence of heteromeric assembly is an expanded range of receptor signaling behaviors. Hetero-tetramers composed of a mix of desensitizing and non-desensitizing subunits exhibit intermediate kinetics not seen with any single subunit type alone (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For instance, a KCTD12/KCTD16 hybrid tetramer produces GABA_B-activated K^+ currents that desensitize moderately and deactivate at a faster rate than KCTD16 alone but slower than KCTD12 alone (pmc.ncbi.nlm.nih.gov). In other words, co-assembly of distinct KCTDs “tunes” the receptor signaling to intermediate levels, providing a fine gradation of inhibitory signaling responses. Bettler and colleagues (2017) demonstrated that mixed KCTD complexes increase the functional repertoire of native GABA_B receptors, allowing neurons to customize the duration and strength of their slow inhibitory postsynaptic currents (IPSCs) (pmc.ncbi.nlm.nih.gov). This combinatorial assembly is likely relevant in brain regions where multiple KCTDs are co-expressed (e.g., hippocampus, cortex), but less so in regions with only one KCTD isoform. In summary, KCTD8 can function both as a homotetrameric regulator and potentially as part of heteromeric KCTD assemblies, giving it the flexibility to contribute to various kinetic profiles of GABA_B signaling. Such versatility underscores a broader principle: simultaneous assembly of distinct KCTD subunits at the receptor increases the molecular and functional diversity of GABA_B receptor signaling (pmc.ncbi.nlm.nih.gov).

It’s also notable that KCTD8 and its family do not universally share all functions of BTB-domain proteins. Many BTB/POZ domain proteins serve as adaptors for Cullin-3 ubiquitin ligase complexes, targeting specific proteins for proteasomal degradation. Some KCTDs (e.g., KCTD11, KCTD6, KCTD5) bind Cullin-3 and function as substrate adaptors in ubiquitination pathways (pmc.ncbi.nlm.nih.gov). However, KCTD8 (along with KCTD12 and KCTD16 in the same clade) has lost the ability to bind Cullin-3 (pmc.ncbi.nlm.nih.gov). Despite the high sequence similarity in the BTB domains, subtle differences (such as in the BTB loop regions) prevent Cullin-3 interaction in these neuronal KCTDs (pmc.ncbi.nlm.nih.gov). Indeed, biochemical assays have shown that clade F KCTDs (KCTD8/12/16) do not recruit Cullin-3, emphasizing that their role is cullin-independent (pmc.ncbi.nlm.nih.gov). This evolutionary divergence likely reflects specialization – instead of participating in ubiquitin ligase complexes, KCTD8 specializes in protein–protein interactions at neurotransmitter receptors. Thus, KCTD8 acts as a signaling adaptor rather than a ubiquitination adaptor, distinguishing its function from some other members of the BTB protein superfamily.

Biological Processes and Pathways Involving KCTD8

Inhibitory neurotransmission: The primary biological process involving KCTD8 is GABAergic inhibitory neurotransmission in the brain. By modulating GABA_B receptor function, KCTD8 influences the slow inhibitory postsynaptic potentials that shape neuronal excitability. GABA_B receptors, when activated (for instance, by synaptically released GABA or pharmacological agonists like baclofen), trigger Gi/o proteins that lead to opening of GIRK (Kir3) potassium channels and inhibition of voltage-gated Ca^2+ channels. These events result in neuronal hyperpolarization and reduced transmitter release, respectively. KCTD8’s role in this pathway is to alter the temporal dynamics of the GABA_B signal – essentially controlling how long and how steady the GABA_B effect persists. In cells expressing KCTD8, GABA_B activation produces a more prolonged inhibitory effect (due to sustained GIRK currents), which can significantly impact network activity such as oscillatory rhythms or synaptic integration over seconds (pubmed.ncbi.nlm.nih.gov). In contrast, cells with KCTD12 experience a quicker fade of the inhibitory effect, potentially allowing faster recovery from inhibition. Therefore, KCTD8 is implicated in maintaining prolonged inhibition in neural circuits, which could be crucial for processes like spike timing regulation, synaptic plasticity (if prolonged hyperpolarization gates plasticity windows), or neurophysiological phenomena like slow-wave oscillations.

Synaptic localization and plasticity: The discovery that KCTD8 helps localize GABA_B receptors to axon terminals in habenular cholinergic neurons (pmc.ncbi.nlm.nih.gov) sheds light on its role in presynaptic modulation. In the medial habenula–interpeduncular nucleus pathway, GABA_B receptors have an unconventional excitatory effect – they enhance presynaptic glutamate release, thereby increasing excitation of target neurons (pmc.ncbi.nlm.nih.gov). KCTD8 (with KCTD12) was found to be required for this effect: without these auxiliary subunits, the GABA_B receptors failed to efficiently populate the presynaptic sites and could not facilitate glutamate release (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This indicates KCTD8 participates in neurotransmitter release modulation and synaptic plasticity. Behaviorally, mice lacking KCTD8/12 in that circuit showed altered aversive memory processing – specifically, stronger activation of the downstream nucleus and impaired extinction of fear memories, presumably because the GABA_B-mediated presynaptic regulation was weakened (pmc.ncbi.nlm.nih.gov). These findings connect KCTD8 to aversive learning pathways and suggest it has a role in modulating synaptic strength and neural network activity underlying certain behaviors. Although this is one specialized circuit, it exemplifies how KCTD8 can influence higher-order processes (memory, emotion) via its control of GABA_B receptor localization and signaling. It is reasonable to suspect that in other brain regions, KCTD8 might similarly affect how GABA_B receptors contribute to synaptic plasticity, neuronal oscillations, or network excitability – topics that are active areas of neuroscience research.

Pharmacological and therapeutic context: KCTD8’s influence on GABA_B receptor pharmacology is also noteworthy. By “determining the pharmacology” of the receptor response (www.ncbi.nlm.nih.gov), KCTD8 can affect how receptors respond to agonists or allosteric modulators. Experiments have shown that auxiliary subunits can slightly shift potency or efficacy of GABA_B agonists and alter the profile of allosteric modulator drugs (www.ncbi.nlm.nih.gov). This means that drugs targeting GABA_B receptors (used for muscle spasticity, pain, addiction, etc.) might have variable effects depending on which KCTD isoforms are present. As such, understanding KCTD8 distribution could inform pharmacotherapy – for instance, brain regions with KCTD8 may experience more sustained GABA_B-mediated drug effects. From a drug development perspective, the unique interfaces between KCTD8 and the GABA_B receptor or G-protein present potential targets for novel modulators. A 2016 authoritative review noted that the complex protein architecture of GABA_B receptors (including accessory subunits like KCTDs) offers new opportunities for therapeutic intervention in neurological and psychiatric disorders (www.nature.com). In principle, one could envision small molecules that disrupt or enhance KCTD8–receptor interaction, thereby prolonging or shortening GABA_B signals in specific circuits as a therapeutic strategy (though no such drug exists yet). Thus, KCTD8 sits at the intersection of basic neuroscience and potential clinical relevance, as part of the broader effort to fine-tune GABAergic signaling in disease contexts.

Emerging Research and Broader Implications

While KCTD8 is best known for its role in the nervous system, recent studies suggest it may have broader biological significance, including in contexts outside classical GABA_B signaling. Remarkably, KCTD8 has emerged in cancer research as a putative tumor suppressor: a 2024 study reported that KCTD8 is frequently silenced by DNA methylation in hepatocellular carcinoma (HCC) (pmc.ncbi.nlm.nih.gov). Approximately 45% of human HCC tumor samples showed hypermethylation of the KCTD8 gene, correlating with reduced KCTD8 expression (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This epigenetic loss of KCTD8 was associated with enhanced activation of the PI3K–AKT signaling pathway in the cancer cells and more aggressive tumor growth (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Functional assays confirmed that restoring KCTD8 expression in HCC cells suppressed their growth in vitro and in mouse xenografts, by attenuating PI3K/AKT signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The study identified KCTD8 as a novel tumor-suppressive factor in liver cancer, and its methylation status was proposed as an independent poor prognostic biomarker for HCC patients (pmc.ncbi.nlm.nih.gov). This finding expands the relevance of KCTD8 beyond neuroscience, suggesting it interacts with cell-signaling networks like PI3K/AKT. The mechanism is still being uncovered – KCTD8 was found to bind IMPDH2 (inosine monophosphate dehydrogenase 2) in HCC cells, an enzyme that can influence nucleotide pools and is linked to PI3K signaling, hinting that KCTD8 might normally restrain proliferative signaling via protein–protein interactions outside the nervous system (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, loss of KCTD8 removes a brake on PI3K–AKT pathway activity in liver cells, thereby promoting cancer cell survival and proliferation (pmc.ncbi.nlm.nih.gov). This unexpected role in cancer biology underscores that KCTD8’s “auxiliary” functions may extend to other receptors or signaling proteins beyond GABA_B, although GABA_B itself is not thought to play a role in liver physiology.

Additionally, KCTD8 (and other KCTDs) have been detected in certain non-neuronal tissues and contexts, implying potential roles that are not yet well-characterized (pubmed.ncbi.nlm.nih.gov). For instance, KCTD proteins have been found in some immune or endocrine tissues where GABA_B receptors are minimally expressed, raising the possibility that they might partner with different signaling proteins or have scaffolding roles in protein complexes unrelated to neurotransmission (pubmed.ncbi.nlm.nih.gov). KCTD15, another family member, inhibits a transcription factor (AP-2α) during embryonic development (pmc.ncbi.nlm.nih.gov), showing that KCTDs can operate in the nucleus as well. While no direct evidence yet places KCTD8 in such a role, these examples encourage a broader view: KCTD8 might have “moonlighting” functions in cellular pathways beyond synapses. Its proven interaction with IMPDH2 in cancer cells is one clue that KCTD8 can engage in protein networks regulating cell metabolism or growth. Future research may uncover whether KCTD8 influences other GPCRs or signaling complexes, or whether it partakes in ubiquitin-independent protein regulation in different cell types.

Clinical and research implications: Understanding KCTD8’s function has implications for neurological disorders. KCTD12 (an auxiliary subunit of the same family) has been linked to psychiatric conditions – for example, KCTD12 gene variants and expression changes are associated with mood disorders and schizophrenia in some studies (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), and Kctd12-knockout mice exhibit antidepressant-like behavior changes (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). While KCTD8 has not been as directly implicated in human neurological disorders yet, its involvement in the habenular pathway hints at a possible role in disorders of aversive behavior (such as addiction or depression, where habenula circuitry is often dysregulated). The fact that knockout of KCTD8/12 altered fear memory extinction in mice suggests that modulating KCTD8 function could potentially affect anxiety or post-traumatic stress disorder (though this remains speculative). On the oncology side, if the findings in HCC are corroborated, KCTD8 methylation might serve as a biomarker for cancer prognosis, and demethylating agents or gene therapies could be explored to restore its expression in tumors. More immediately, the HCC study positions KCTD8 as a part of the PI3K/AKT regulatory axis, opening new questions about whether KCTD8 polymorphisms or expression changes occur in other cancers or metabolic diseases.

From an expert perspective, the discovery of KCTD8 and related subunits has fundamentally expanded our understanding of GABA_B receptor function. Receptor complexes are now seen as modular assemblies, where core subunits provide baseline function and auxiliary subunits (like KCTD8) fine-tune signaling properties (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). As noted by Bettler and colleagues, this added molecular complexity endows inhibitory synapses with a richer repertoire of responses and plasticity, which can be exploited for more targeted interventions (pmc.ncbi.nlm.nih.gov). In sum, KCTD8 is a BTB-domain adaptor that specializes in regulating GABA_B G-protein signaling – prolonging inhibitory signals and aiding receptor trafficking – and it may also play unanticipated roles in cell signaling, as evidenced by recent cancer research. Continuing studies (especially those published in 2023–2024) highlight KCTD8’s multifaceted importance: in the brain, it helps shape synaptic inhibition and behavior, and beyond the brain, it might act as a tumor suppressor and signaling regulator. Such insights underscore the potential of KCTD8 as a target for research in both neuroscience and disease contexts, warranting further investigation into its molecular partners and regulatory mechanisms.

References:

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  16. AnnotationURLCitation(end_index=4724, start_index=4569, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  17. AnnotationURLCitation(end_index=5579, start_index=5465, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=are%20unknown,Here%20we%20addressed')
  18. AnnotationURLCitation(end_index=5857, start_index=5687, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  19. AnnotationURLCitation(end_index=6108, start_index=5953, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  20. AnnotationURLCitation(end_index=6541, start_index=6386, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  21. AnnotationURLCitation(end_index=6851, start_index=6696, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  22. AnnotationURLCitation(end_index=7276, start_index=7121, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  23. AnnotationURLCitation(end_index=7608, start_index=7438, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  24. AnnotationURLCitation(end_index=7932, start_index=7787, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=the%20receptor%20response,and%20acquisition%20of%20the%20T%2FNFLEQ')
  25. AnnotationURLCitation(end_index=8281, start_index=8136, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=the%20receptor%20response,and%20acquisition%20of%20the%20T%2FNFLEQ')
  26. AnnotationURLCitation(end_index=8879, start_index=8749, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=GABA,comprising%20a%20T1%20tetramerization%20domain')
  27. AnnotationURLCitation(end_index=9308, start_index=9144, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=reveal%20that%20KCTD12%2FKCTD16%20hetero,one%20min%29%20KCTD12%2FKCTD16%20hetero')
  28. AnnotationURLCitation(end_index=9919, start_index=9749, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  29. AnnotationURLCitation(end_index=10054, start_index=9920, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=which%20binds%20to%20GABA,to%20the%20H1%20domains%20but')
  30. AnnotationURLCitation(end_index=10320, start_index=10150, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  31. AnnotationURLCitation(end_index=10672, start_index=10524, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=auxiliary%20subunits%20constitute%20receptor%20subtypes,12b%20mediate')
  32. AnnotationURLCitation(end_index=11014, start_index=10866, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=auxiliary%20subunits%20constitute%20receptor%20subtypes,12b%20mediate')
  33. AnnotationURLCitation(end_index=11170, start_index=11015, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  34. AnnotationURLCitation(end_index=11404, start_index=11274, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=GABA,comprising%20a%20T1%20tetramerization%20domain')
  35. AnnotationURLCitation(end_index=11560, start_index=11405, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  36. AnnotationURLCitation(end_index=12403, start_index=12259, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=the%20KCTDs%20in%20the%20mouse,KCTD8%20and%2012b%20a%20restricted')
  37. AnnotationURLCitation(end_index=12759, start_index=12615, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=the%20KCTDs%20in%20the%20mouse,KCTD8%20and%2012b%20a%20restricted')
  38. AnnotationURLCitation(end_index=13086, start_index=12936, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=brain%2C%20KCTD12%20and%2016%20have,suggesting%20that%20the%20role%20of')
  39. AnnotationURLCitation(end_index=13433, start_index=13289, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=the%20KCTDs%20in%20the%20mouse,KCTD8%20and%2012b%20a%20restricted')
  40. AnnotationURLCitation(end_index=13673, start_index=13516, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=brain%2C%20KCTD12%20and%2016%20have,In%20summary%2C%20our%20findings%20support')
  41. AnnotationURLCitation(end_index=14060, start_index=13910, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=brain%2C%20KCTD12%20and%2016%20have,suggesting%20that%20the%20role%20of')
  42. AnnotationURLCitation(end_index=14474, start_index=14313, title='KCTD8 potassium channel tetramerization domain containing 8 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/386617#:~:text=Expression%20Biased%20expression%20in%20brain,other%20tissues%20See%20more%20Orthologs')
  43. AnnotationURLCitation(end_index=15138, start_index=14983, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=selectively%20express%20one%20KCTD%20at,We%20propose%20that%20the%20distinct')
  44. AnnotationURLCitation(end_index=15613, start_index=15452, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  45. AnnotationURLCitation(end_index=15732, start_index=15614, 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=GABA_,related%20memory%20processes')
  46. AnnotationURLCitation(end_index=16237, start_index=16076, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  47. AnnotationURLCitation(end_index=16356, start_index=16238, 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=GABA_,related%20memory%20processes')
  48. AnnotationURLCitation(end_index=16791, start_index=16630, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  49. AnnotationURLCitation(end_index=17099, start_index=16912, 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=within%20the%20habenulo%E2%80%93interpeduncular%20pathway%20in,proteins%20in%20enriching%20the%20axonal')
  50. AnnotationURLCitation(end_index=17938, start_index=17783, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=selectively%20express%20one%20KCTD%20at,We%20propose%20that%20the%20distinct')
  51. AnnotationURLCitation(end_index=18626, start_index=18469, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  52. AnnotationURLCitation(end_index=18984, start_index=18816, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=receptors%20also%20associate%20with%20hetero,one%20min%29%20KCTD12%2FKCTD16%20hetero')
  53. AnnotationURLCitation(end_index=19314, start_index=19170, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=KCTD8%20and%20KCTD16%20also%20interacted,also%20yielded%20a%20BRET%20signal')
  54. AnnotationURLCitation(end_index=19464, start_index=19315, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=consisting%20of%20KCTD8%2C%20KCTD12%2C%20and,oligomeric%20configurations%20%5B14')
  55. AnnotationURLCitation(end_index=19802, start_index=19658, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=KCTD8%20and%20KCTD16%20also%20interacted,also%20yielded%20a%20BRET%20signal')
  56. AnnotationURLCitation(end_index=19942, start_index=19803, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=involved%20in%20shaping%20GABA_,Nluc%2C%20and%20the%20strongest%20with')
  57. AnnotationURLCitation(end_index=20281, start_index=20139, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=KCTD16%20but%20not%20with%20KCTD12,Nluc%2C%20and%20the%20strongest%20with')
  58. AnnotationURLCitation(end_index=20428, start_index=20282, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=with%20KCTD8%2C%20KCTD12%2C%20and%20KCTD16,luminescence%20experiments.%20Thus')
  59. AnnotationURLCitation(end_index=20860, start_index=20696, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=reveal%20that%20KCTD12%2FKCTD16%20hetero,one%20min%29%20KCTD12%2FKCTD16%20hetero')
  60. AnnotationURLCitation(end_index=21018, start_index=20861, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  61. AnnotationURLCitation(end_index=21384, start_index=21220, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=reveal%20that%20KCTD12%2FKCTD16%20hetero,one%20min%29%20KCTD12%2FKCTD16%20hetero')
  62. AnnotationURLCitation(end_index=21957, start_index=21800, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  63. AnnotationURLCitation(end_index=22709, start_index=22552, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  64. AnnotationURLCitation(end_index=23226, start_index=23084, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=and%20F%20,the%20extensive%20literature%20functional%20and')
  65. AnnotationURLCitation(end_index=23470, start_index=23334, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=Taking%20into%20account%20the%20close,and%20of%20the')
  66. AnnotationURLCitation(end_index=23771, start_index=23635, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=Taking%20into%20account%20the%20close,and%20of%20the')
  67. AnnotationURLCitation(end_index=24069, start_index=23927, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=and%20F%20,the%20extensive%20literature%20functional%20and')
  68. AnnotationURLCitation(end_index=25673, start_index=25518, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=properties.%20KCTD12%20and%20,comprising%20a%20T1%20tetramerization%20domain')
  69. AnnotationURLCitation(end_index=26423, start_index=26262, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  70. AnnotationURLCitation(end_index=26826, start_index=26691, 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=GABA_,potentiation%20of%20glutamate%20release%20and')
  71. AnnotationURLCitation(end_index=27202, start_index=27041, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  72. AnnotationURLCitation(end_index=27321, start_index=27203, 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=GABA_,related%20memory%20processes')
  73. AnnotationURLCitation(end_index=27849, start_index=27698, 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=reversed%20the%20changes%20in%20axonal,related%20memory%20processes')
  74. AnnotationURLCitation(end_index=28810, start_index=28640, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  75. AnnotationURLCitation(end_index=29218, start_index=29048, title='CDD Conserved Protein Domain Family: H1_KCTD8', type='url_citation', url='https://www.ncbi.nlm.nih.gov/Structure/cdd/cd22218#:~:text=protein%2C%20is%20an%20auxiliary%20subunit,not%20be%20involved%20in%20desensitization')
  76. AnnotationURLCitation(end_index=30124, start_index=29963, title='Organization and functions of mGlu and GABAB receptor complexes | Nature', type='url_citation', url='https://www.nature.com/articles/nature20566#:~:text=that%20the%20molecular%20complexity%20of,mental%20health%20and%20neurological%20disorders')
  77. AnnotationURLCitation(end_index=31064, start_index=30970, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  78. AnnotationURLCitation(end_index=31376, start_index=31202, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=Results%3A%20KCTD8%20was%20methylated%20in,vivo%20via%20inhibiting%20PI3K%2FAKT%20pathway')
  79. AnnotationURLCitation(end_index=31471, start_index=31377, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  80. AnnotationURLCitation(end_index=31804, start_index=31630, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=Results%3A%20KCTD8%20was%20methylated%20in,vivo%20via%20inhibiting%20PI3K%2FAKT%20pathway')
  81. AnnotationURLCitation(end_index=31899, start_index=31805, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  82. AnnotationURLCitation(end_index=32244, start_index=32070, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=Results%3A%20KCTD8%20was%20methylated%20in,vivo%20via%20inhibiting%20PI3K%2FAKT%20pathway')
  83. AnnotationURLCitation(end_index=32339, start_index=32245, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  84. AnnotationURLCitation(end_index=32620, start_index=32526, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  85. AnnotationURLCitation(end_index=33249, start_index=33091, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=The%20mechanism%20of%20KCTD8%20in,by%20the%20KCTD8%20antibody%2C%20IMPDH2')
  86. AnnotationURLCitation(end_index=33406, start_index=33250, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=employed%20to%20clarify%20the%20mechanism,The%20results%20showed%20that')
  87. AnnotationURLCitation(end_index=33650, start_index=33556, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  88. AnnotationURLCitation(end_index=34235, start_index=34049, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=reveals%20that%20individual%20KCTD%20proteins,distribution%20patterns%20underlie%20functional%20differences')
  89. AnnotationURLCitation(end_index=34711, start_index=34525, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=reveals%20that%20individual%20KCTD%20proteins,distribution%20patterns%20underlie%20functional%20differences')
  90. AnnotationURLCitation(end_index=34990, start_index=34813, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=particular%2C%20KCTD15%20inhibits%20neural%20crest,involved%20in%20the%20ubiquitination%20and')
  91. AnnotationURLCitation(end_index=36047, start_index=35890, 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,Transl%20Psychiatry%205%3Ae510')
  92. AnnotationURLCitation(end_index=36188, start_index=36048, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=KCTD%20Hetero,that%20assemble%20into%20molecularly%20and')
  93. AnnotationURLCitation(end_index=36431, start_index=36260, title='Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25689571/#:~:text=Altered%20emotionality%20and%20neuronal%20excitability,well%20as%20auxiliary%20KCTD8%2C%2012')
  94. AnnotationURLCitation(end_index=36583, start_index=36432, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=The%20BTB%20%28Bric,physiological%20processes%20such%20as%20protein')
  95. AnnotationURLCitation(end_index=37944, start_index=37843, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=,Google%20Scholar')
  96. AnnotationURLCitation(end_index=38102, start_index=37945, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  97. AnnotationURLCitation(end_index=38467, start_index=38310, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  98. AnnotationURLCitation(end_index=39423, start_index=39322, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=,Google%20Scholar')
  99. AnnotationURLCitation(end_index=39668, start_index=39563, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=,PMC%20free%20article')
  100. AnnotationURLCitation(end_index=39990, start_index=39842, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=auxiliary%20subunits%20constitute%20receptor%20subtypes,12b%20mediate')
  101. AnnotationURLCitation(end_index=40125, start_index=39991, title='Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/23035119/#:~:text=which%20binds%20to%20GABA,to%20the%20H1%20domains%20but')
  102. AnnotationURLCitation(end_index=40469, start_index=40305, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=reveal%20that%20KCTD12%2FKCTD16%20hetero,one%20min%29%20KCTD12%2FKCTD16%20hetero')
  103. AnnotationURLCitation(end_index=40627, start_index=40470, title='KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6596860/#:~:text=duration%20of%20slow%20IPSCs,current%20responses%20in%20the%20hippocampus')
  104. AnnotationURLCitation(end_index=40974, start_index=40813, 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=remains%20unclear%20whether%20and%20how,a%20significant%20decrease%20in%20the')
  105. AnnotationURLCitation(end_index=41093, start_index=40975, 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=GABA_,related%20memory%20processes')
  106. AnnotationURLCitation(end_index=41495, start_index=41321, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=Results%3A%20KCTD8%20was%20methylated%20in,vivo%20via%20inhibiting%20PI3K%2FAKT%20pathway')
  107. AnnotationURLCitation(end_index=41590, start_index=41496, title='Epigenetic silencing of KCTD8 promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11370965/#:~:text=,in%20HCC')
  108. AnnotationURLCitation(end_index=41944, start_index=41800, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=KCTD8%20and%20KCTD16%20also%20interacted,also%20yielded%20a%20BRET%20signal')
  109. AnnotationURLCitation(end_index=42084, start_index=41945, title='KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family', type='url_citation', url='https://www.mdpi.com/1422-0067/24/18/14317#:~:text=involved%20in%20shaping%20GABA_,Nluc%2C%20and%20the%20strongest%20with')
  110. AnnotationURLCitation(end_index=42401, start_index=42240, title='Organization and functions of mGlu and GABAB receptor complexes | Nature', type='url_citation', url='https://www.nature.com/articles/nature20566#:~:text=that%20the%20molecular%20complexity%20of,mental%20health%20and%20neurological%20disorders')
  111. AnnotationURLCitation(end_index=42737, start_index=42601, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=Taking%20into%20account%20the%20close,and%20of%20the')
  112. AnnotationURLCitation(end_index=42880, start_index=42738, title='Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4431850/#:~:text=and%20F%20,the%20extensive%20literature%20functional%20and')
  113. AnnotationURLCitation(end_index=43240, start_index=43096, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=the%20KCTDs%20in%20the%20mouse,KCTD8%20and%2012b%20a%20restricted')
  114. AnnotationURLCitation(end_index=43391, start_index=43241, title='Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21452234/#:~:text=brain%2C%20KCTD12%20and%2016%20have,suggesting%20that%20the%20role%20of')