IplA is the sole inositol 1,4,5-trisphosphate/ryanodine receptor family member in Dictyostelium discoideum and the only recognizable homolog of the metazoan IP3 receptor in this organism. It is a very large (3177 aa) multi-pass endoplasmic reticulum membrane protein with a long cytoplasmic N-terminal region containing predicted InsP3-binding residues and a C-terminal six-transmembrane channel domain, and it assembles into the intracellular ligand-gated calcium-release channel that governs Ca2+ efflux from ER stores into the cytosol. Genetic ablation of iplA abolishes the chemoattractant (cAMP/folate)-stimulated Ca2+ entry and the accompanying rise in free cytosolic Ca2+, while leaving resting cytosolic Ca2+, cAMP chemotaxis, cGMP production and MAP kinase signaling intact. IplA is specifically required for chemotaxis up spatial Ca2+ gradients and contributes to a wide range of Ca2+-dependent processes, including natural aggregation, arachidonate chemotaxis, AprA-mediated chemorepulsion, mechanosensory Ca2+ bursts in slugs, regulation of blebbing, DIF-induced autophagic cell death with cellulose shell synthesis, and polyphosphate/IP3-Ca2+ feedback inhibition of proliferation. Although it is clearly a Ca2+ channel of the InsP3R/RyR family, direct biochemical demonstration that IplA is gated by InsP3 is still lacking.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030659 cytoplasmic vesicle membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference placing IplA in vesicle membranes. IP3-receptor family channels reside chiefly in the ER membrane but are also found in vesicle membranes, so this is plausible but not the principal, best-supported location. Reason: The endoplasmic reticulum membrane is the established primary location for IplA; a cytoplasmic vesicle membrane pool is plausible for an IP3R-family channel but is secondary to the core ER-membrane localization. Supporting Evidence: PMID:22375061 usually located in the membrane of endoplasmic reticulum and vesicles, but are also found at low levels in the plasma membrane |
| GO:0005220 inositol 1,4,5-trisphosphate-gated calcium channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO transfer of the specific mammalian ITPR molecular function. IplA is the sole IP3R-family homolog and functions as an intracellular Ca2+-release channel, but direct biochemical evidence that it is gated by InsP3 is explicitly lacking, so the specific InsP3-gated term over-reaches what has been demonstrated. Reason: The demonstrated activity is that of an (intracellular) calcium channel; InsP3-gating is inferred from sequence homology and conserved binding residues but has not been shown biochemically. Generalizing the overly specific InsP3-gated term to calcium channel activity better matches the evidence. Proposed replacements: calcium channel activity Supporting Evidence: PMID:10970875 biochemical evidence that IplA is an InsP 3 receptor is still lacking PMID:40295210 IplA, a Dictyostelium protein analogous to the mammalian IP3 receptor, is a ligand-gated calcium channel responsible for calcium release from the endoplasmic reticulum |
| GO:0005262 calcium channel activity | IEA GO_REF:0000002 | ACCEPT | Summary: IplA is an intracellular ligand-gated calcium-release channel; ablation of iplA abolishes chemoattractant-stimulated Ca2+ fluxes. This is the core molecular function of the gene product. Reason: Calcium channel activity is the well-supported core function, consistent with the InsP3R/RyR family assignment and the loss of Ca2+ fluxes in iplA-null cells. Supporting Evidence: PMID:10970875 InsP 3 /RyR receptor family of ligand-gated Ca 2+ channels PMID:40295210 IplA, a Dictyostelium protein analogous to the mammalian IP3 receptor, is a ligand-gated calcium channel responsible for calcium release from the endoplasmic reticulum |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Generic ARBA-derived cytoplasm localization. Not incorrect (the cytoplasmic N-terminal region is large) but uninformative relative to the specific ER-membrane localization. Reason: Cytoplasm is a high-level, uninformative location for a multi-pass ER membrane channel; the endoplasmic reticulum membrane term captures the biology better. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: The endoplasmic reticulum is the established compartment for IplA, consistent with its role as an ER Ca2+-store release channel. Reason: ER localization is supported by the UniProt subcellular location and by the protein's function in releasing Ca2+ from ER stores. Supporting Evidence: PMID:18077554 a ligand-gated channel governing Ca(2+) efflux from endoplasmic reticulum stores |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The most precise and best-supported location for IplA, a multi-pass ER membrane channel that releases Ca2+ from ER stores into the cytosol. Reason: ER membrane localization matches the UniProt subcellular location, the six-transmembrane topology, and the ER Ca2+-store release function. Supporting Evidence: PMID:40295210 IplA, a Dictyostelium protein analogous to the mammalian IP3 receptor, is a ligand-gated calcium channel responsible for calcium release from the endoplasmic reticulum |
| GO:0006816 calcium ion transport | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium ion transport is a direct consequence of IplA channel activity and is central to its function. Reason: As a Ca2+ channel, IplA mediates calcium ion transport; ablation abolishes chemoattractant-stimulated Ca2+ fluxes. Supporting Evidence: PMID:10970875 Ca(2+) entry in response to chemoattractants is abolished |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane localization, subsumed by the more specific endoplasmic reticulum membrane term. Reason: Membrane is an uninformative high-level location; the ER membrane annotation is the informative one. |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Transmembrane movement of Ca2+ across the ER membrane is the core activity of this channel. Reason: IplA conducts Ca2+ across the ER membrane; this process directly reflects its channel function. Supporting Evidence: PMID:18077554 a ligand-gated channel governing Ca(2+) efflux from endoplasmic reticulum stores |
| GO:0070679 inositol 1,4,5 trisphosphate binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO transfer based on the IP3R-family InsP3-binding domain. IplA retains predicted InsP3-binding residues, but direct biochemical InsP3 binding has not been demonstrated for this divergent protein. Reason: InsP3 binding is inferred from conserved sequence features; experimental verification is lacking (biochemical evidence that IplA is an InsP3 receptor is still lacking), so it should not be treated as an established core function. Supporting Evidence: PMID:10970875 biochemical evidence that IplA is an InsP 3 receptor is still lacking |
| GO:0019722 calcium-mediated signaling | IMP PMID:40295210 Intracellular Calcium Responses to External Calcium Stimuli ... | ACCEPT | Summary: iplA-null cells show a reduced proportion of cells mounting an intracellular Ca2+ response to external calcium, placing IplA within calcium-mediated signaling. Reason: Directly supported by the phenotype of iplA-null cells in calcium-signaling assays; this is closely tied to the core channel function. Supporting Evidence: PMID:40295210 only approximately 60% of iplA-null cells were responsive to the external calcium stimuli PMID:40295210 IplA-related signaling pathways are involved in regulating intracellular calcium levels in response to external calcium stimuli |
| GO:0006935 chemotaxis | IMP PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | KEEP AS NON CORE | Summary: iplA-null cells retain normal chemotaxis to cAMP but specifically lose chemotaxis up spatial Ca2+ gradients. The generic chemotaxis term is imprecise; the specific Ca2+-gradient role is captured by the cell-motility-in-response-to-calcium term. Reason: IplA is not required for chemotaxis generally (cAMP chemotaxis is normal); its role is restricted to Ca2+-gradient chemotaxis, so the broad term is a non-core, over-general description. Supporting Evidence: PMID:22375061 cells lose the capacity to undergo chemotaxis in response to a spatial gradient |
| GO:0071260 cellular response to mechanical stimulus | IMP PMID:35859163 Calcium responses to external mechanical stimuli in the mult... | KEEP AS NON CORE | Summary: IplA contributes to Ca2+ bursts triggered by mechanical stimulation of slugs, one of two pathways (ER release via IplA plus extracellular influx) mediating mechanosensory Ca2+ signaling. Reason: Supported by reduced mechanically induced Ca2+ bursts in iplA-null slugs; a downstream physiological role of the channel rather than its core molecular function. Supporting Evidence: PMID:35859163 response to mechanical stimuli are partially mediated by PMID:35859163 the calcium channel, IplA, the homolog of the IP3 receptor, is essential for its elevation |
| GO:0140986 G protein-coupled chemorepellent receptor signaling pathway | IMP PMID:30462573 An endogenous chemorepellent directs cell movement by inhibi... | KEEP AS NON CORE | Summary: iplA-null cells fail to move away from the chemorepellent AprA, implicating IplA in the AprA chemorepulsion signaling pathway. Reason: Supported by the AprA chemorepulsion phenotype of iplA-null cells; a downstream Ca2+-dependent process rather than the core channel function. Supporting Evidence: PMID:30462573 iplA− cells did not move away from AprA PMID:30462573 IplA and PkcA, although not necessary for chemoattraction toward cAMP, are necessary for chemorepulsion from AprA |
| GO:0016020 membrane | ISS PMID:10970875 Ca(2+) signalling is not required for chemotaxis in Dictyost... | KEEP AS NON CORE | Summary: Sequence-based (ISS) membrane localization from the predicted multi-pass transmembrane topology. Correct but generic; the ER membrane term is the informative one. Reason: Membrane is a high-level, uninformative location; IplA is more precisely an ER membrane multi-pass channel. Supporting Evidence: PMID:10970875 it is the membrane channel of an intracellular Ca 2+ store |
| GO:1903665 negative regulation of asexual reproduction | IMP PMID:34154396 An Autocrine Negative Feedback Loop Inhibits Dictyostelium d... | KEEP AS NON CORE | Summary: IplA is required for polyphosphate-induced inhibition of proliferation, acting within an autocrine IP3/Ca2+ negative-feedback loop that limits cell density. Reason: Supported by reduced polyphosphate sensitivity and loss of the polyphosphate-triggered cytosolic Ca2+ rise in iplA-null cells; a downstream Ca2+-signaling role rather than the core molecular function. Supporting Evidence: PMID:34154396 inositol 1,4,5-trisphosphate (IP3) receptor-like protein A (IplA), polyphosphate PMID:34154396 Polyphosphate also upregulates cytosolic Ca2+, and this requires GrlD |
| GO:0032060 bleb assembly | IMP PMID:26317626 Microtubule-Mediated Inositol Lipid Signaling Plays Critical... | KEEP AS NON CORE | Summary: iplA-null cells extend blebs more frequently than wild type, implicating IplA (Ca2+ channel) in the regulation of blebbing. Reason: Supported by the increased blebbing phenotype of iplA-null cells; a downstream role in membrane dynamics rather than the core channel function. Supporting Evidence: PMID:26317626 extended blebs more frequently than wild type cells |
| GO:0031152 aggregation involved in sorocarp development | IMP PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | KEEP AS NON CORE | Summary: IplA has a fundamental role in natural aggregation, since iplA-null cells lose the ability to reorient toward the aggregation center at the onset of each natural cAMP wave. Reason: Supported by the natural-aggregation defect of iplA-null cells; a developmental consequence of impaired Ca2+ signaling rather than the core molecular function. Supporting Evidence: PMID:22375061 has a fundamental role in natural aggregation |
| GO:0097231 cell motility in response to calcium ion | IMP PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | ACCEPT | Summary: IplA is essential for chemotaxis in a spatial gradient of Ca2+ while dispensable for cAMP chemotaxis, making it the signature Ca2+-gradient motility component in Dictyostelium. Reason: This is the most specific and distinctive experimentally supported process for iplA, directly reflecting the loss of Ca2+-gradient chemotaxis in null cells. Supporting Evidence: PMID:22375061 mutant of the putative IplA Ca(2+) channel gene, iplA(-), undergoes normal PMID:22375061 cells lose the capacity to undergo chemotaxis in response to a spatial gradient |
| GO:0005509 calcium ion binding | IMP PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | MARK AS OVER ANNOTATED | Summary: Calcium ion binding inferred from the Ca2+-chemotaxis phenotype. As a generic sensor-type binding term it does not capture IplA's function; the informative molecular function is (intracellular) calcium channel activity. Reason: IplA conducts Ca2+ through a channel; annotating generic calcium ion binding (typically an EF-hand sensor function) over-annotates the protein. The channel-activity terms represent the true molecular function. Supporting Evidence: PMID:10970875 InsP 3 /RyR receptor family of ligand-gated Ca 2+ channels |
| GO:0005886 plasma membrane | IDA PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | KEEP AS NON CORE | Summary: A minor plasma-membrane pool is consistent with IP3R-family behavior (these channels are found at low levels in the plasma membrane), but the primary location of IplA is the ER membrane and whether it acts as a plasma-membrane channel remains uncertain. Reason: The curator annotation is retained, but plasma membrane is a minor/uncertain location relative to the ER membrane; mechanistically IplA is considered more likely the channel of an intracellular Ca2+ store. Supporting Evidence: PMID:22375061 usually located in the membrane of endoplasmic reticulum and vesicles, but are also found at low levels in the plasma membrane PMID:10970875 it is the membrane channel of an intracellular Ca 2+ store |
| GO:0030659 cytoplasmic vesicle membrane | IDA PMID:22375061 The IplA Ca2+ channel of Dictyostelium discoideum is necessa... | KEEP AS NON CORE | Summary: A vesicle-membrane pool is plausible for an IP3R-family channel, though the ER membrane is the principal location. Reason: Retained as a secondary location; the core, best-supported localization is the endoplasmic reticulum membrane. Supporting Evidence: PMID:22375061 usually located in the membrane of endoplasmic reticulum and vesicles, but are also found at low levels in the plasma membrane |
| GO:0034670 chemotaxis to arachidonate | IMP PMID:18202452 Arachidonic acid is a chemoattractant for Dictyostelium disc... | KEEP AS NON CORE | Summary: Arachidonic acid is a chemoattractant whose Ca2+-dependence differs between wild type and the iplA-null HM1049 strain, implicating IplA in the Ca2+-dependent arm of arachidonate chemotaxis. Reason: Supported by the altered EGTA sensitivity of arachidonate chemotaxis in iplA-null cells; a downstream Ca2+-dependent process rather than the core channel function. Supporting Evidence: PMID:18202452 iplA gene encoding a putative Ins(1,4,5)P3 -receptor had been knocked out PMID:18202452 chemotaxis was only slightly affected by EGTA |
| GO:0051209 release of sequestered calcium ion into cytosol | IMP PMID:18359017 Mechano-chemical signaling maintains the rapid movement of D... | ACCEPT | Summary: As the ER IP3R-family channel, IplA governs Ca2+ efflux from ER stores into the cytosol and contributes to the intracellular-source Ca2+ transients seen during mechanochemical signaling. Reason: Release of sequestered Ca2+ into the cytosol is the direct physiological readout of IplA channel activity and is well supported across the literature. Supporting Evidence: PMID:18077554 a ligand-gated channel governing Ca(2+) efflux from endoplasmic reticulum stores PMID:18359017 small, brief, Ca2+ transients in randomly moving wild-type |
| GO:0030244 cellulose biosynthetic process | IMP PMID:18077554 The inositol 1,4,5-trisphosphate receptor is required to sig... | KEEP AS NON CORE | Summary: The iplA-null mutation prevents DIF-induced cellulose shell synthesis around dying cells, consistent with IP3R/Ca2+ control of genes governing cellulose synthesis. Reason: Supported by the loss of cellulose shell synthesis in iplA-null cells under DIF; an indirect downstream, transcriptionally mediated consequence of Ca2+ signaling rather than a core molecular function. Supporting Evidence: PMID:18077554 The iplA − mutation prevented cellulose shell synthesis around cells subjected to DIF |
| GO:0048102 autophagic cell death | IMP PMID:18077554 The inositol 1,4,5-trisphosphate receptor is required to sig... | KEEP AS NON CORE | Summary: Inactivation of iplA, the only IP3R gene in Dictyostelium, prevents DIF-induced autophagic cell death, defining an IplA/IP3R-dependent Ca2+ pathway for ACD. Reason: Strongly supported by the ACD-resistant phenotype of iplA-null cells; a downstream Ca2+-dependent developmental process rather than the core channel function. Supporting Evidence: PMID:18077554 inactivation of the iplA gene, the only gene encoding an inositol PMID:18077554 a ligand-gated channel governing Ca(2+) efflux from endoplasmic reticulum stores |
| GO:0006816 calcium ion transport | IMP PMID:17077123 Influx of extracellular Ca2+ is necessary for electrotaxis i... | ACCEPT | Summary: IplA is described as the gene responsible for chemoattractant-induced cytosolic Ca2+ increase. Notably, this same study shows iplA is NOT required for electrotaxis-associated Ca2+ influx, underscoring that IplA mediates a specific (chemoattractant-linked) calcium transport route. Reason: Calcium ion transport is supported by IplA's established role in the chemoattractant-induced cytosolic Ca2+ increase; note that this paper also shows the electrotaxis Ca2+ rise is iplA-independent, so the transport role is chemoattractant-specific. Supporting Evidence: PMID:17077123 Different roles of the iplA gene in chemoattractant-induced |
| GO:0006816 calcium ion transport | IMP PMID:10970875 Ca(2+) signalling is not required for chemotaxis in Dictyost... | ACCEPT | Summary: Disruption of iplA abolishes chemoattractant-stimulated Ca2+ entry and the cytosolic Ca2+ rise, directly demonstrating a role in calcium ion transport. Reason: Strong experimental (IMP) support for calcium ion transport from the original characterization of the iplA-null mutant. Supporting Evidence: PMID:10970875 Ca(2+) entry in response to chemoattractants is abolished |
| GO:0015085 calcium ion transmembrane transporter activity | ISS PMID:10970875 Ca(2+) signalling is not required for chemotaxis in Dictyost... | ACCEPT | Summary: Sequence homology places IplA in the InsP3R/RyR family of ligand-gated Ca2+ channels, and the null phenotype supports Ca2+ transmembrane transporter activity. Reason: A core molecular-function annotation consistent with the channel/transporter role; supported by both sequence family placement and the loss of Ca2+ fluxes in null cells. Supporting Evidence: PMID:10970875 InsP 3 /RyR receptor family of ligand-gated Ca 2+ channels |
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