gcy-8 encodes a receptor-type (transmembrane) guanylate cyclase expressed exclusively in the AFD thermosensory neurons of C. elegans. With GCY-8, GCY-18 and GCY-23 it forms an AFD-specific subfamily; each has an extracellular domain with little similarity to mammalian receptor guanylyl cyclases, a single transmembrane helix, an intracellular kinase-homology domain predicted to be catalytically inactive, and a C-terminal guanylate cyclase domain that converts GTP to cGMP. GCY-8 is concentrated at the AFD sensory ending (the microvillar receptive ending). The three AFD cyclases act partly redundantly to supply the cGMP that opens the TAX-2/TAX-4 cyclic nucleotide-gated channel in response to warming; triple mutants are athermotactic and lack temperature-evoked AFD currents. The individual cyclases have distinct roles. GCY-8 alone among the three is required for AFD responses to rapid temperature changes around the cultivation temperature and for execution of isothermal tracking, whereas in migration assays GCY-18 makes the largest single contribution to thermotaxis at 20 and 25 degrees. Its basal cyclase activity is directly inhibited by extracellular chloride, which is regulated by the glial K/Cl transporter KCC-3; through this, GCY-8-derived cGMP also controls the length of AFD receptive-ending microvilli by antagonizing the actin regulator WSP-1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001653 peptide receptor activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PANTHER IBA transfer of peptide receptor activity from vertebrate natriuretic peptide receptor guanylyl cyclases. Reason: GCY-8 is an AFD-specific receptor guanylyl cyclase of the GCY-8/18/23 subfamily whose extracellular domain shows little homology to human guanylyl cyclases; no peptide ligand is known. The only identified extracellular regulator of this subfamily is inhibitory chloride acting on GCY-8. Peptide-receptor activity is a natriuretic-peptide-receptor-specific property not demonstrated for this nematode clade. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000229249 SUPPORTS SOURCE BUT NOT TARGET Peptide-receptor activity is grounded in vertebrate natriuretic peptide receptor guanylyl cyclases (NPR-A/NPR-B); the C. elegans sensory receptor guanylyl cyclase radiation has no demonstrated peptide ligand. Supporting Evidence: PMID:16415369 GCY-8, -18, and -23 showed little homology to human guanylyl cyclases in the extracellular domain |
| GO:0004383 guanylate cyclase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA guanylate cyclase activity; GCY-8 has a conserved C-terminal class-4 guanylate cyclase domain and belongs to the receptor guanylyl cyclase clade. Core. Supporting Evidence: file:worm/gcy-8/gcy-8-uniprot.txt Guanylate cyclase involved in the production of the second messenger cGMP |
| GO:0004383 guanylate cyclase activity | IDA PMID:27062922 A Glial K/Cl Transporter Controls Neuronal Receptive Ending ... | ACCEPT | Summary: Direct assay: cells expressing GCY-8 show significant basal guanylyl cyclase activity, which is inhibited by extracellular Cl− (IC50 ~60 mM). Core molecular function. Supporting Evidence: PMID:27062922 First, while hNPR1 has essentially no basal activity, as previously reported, GCY-8-expressing cells show significant activity, as predicted by our genetic data. PMID:27062922 Strikingly, we found that Cl− ions, but not K+ or other anions, are potent inhibitors of GCY-8 cyclase activity and cGMP production |
| GO:0004383 guanylate cyclase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated (EC 4.6.1.2/RHEA) guanylate cyclase activity, consistent with domain architecture. Core. Supporting Evidence: file:worm/gcy-8/gcy-8-uniprot.txt Guanylate cyclase involved in the production of the second messenger cGMP |
| GO:0004383 guanylate cyclase activity | ISS PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: ISS guanylate cyclase activity from the paper identifying the AFD GCY-8/18/23 subfamily, which proposes that these cyclases transduce temperature into cGMP for the TAX-4 channel. Core. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | REMOVE | Summary: InterPro mapping from the kinase-homology domain to protein kinase activity. Reason: In receptor guanylyl cyclases the kinase-homology domain is a regulatory pseudokinase; UniProt states the GCY-8 kinase domain is predicted to be catalytically inactive, and no kinase activity has been reported. The InterPro2GO mapping for the Ser/Thr/Tyr kinase domain is not applicable to this pseudokinase. Supporting Evidence: file:worm/gcy-8/gcy-8-uniprot.txt The protein kinase domain is predicted to be catalytically inactive. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro ATP binding from the kinase-homology domain. The pseudokinase domain of receptor guanylyl cyclases may bind ATP as a regulator of cyclase activity, but this is untested here. Non-core. Supporting Evidence: PMID:16415369 Three serine and threonine residues that have been reported to be reversibly phosphorylated in mammalian guanylyl cyclases were also conserved in the kinase homology domains of the GCY-8, GCY-18, and GCY-23 guanylyl cyclases. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GCY-8 is a single-pass type I membrane protein; plasma membrane is correct, but the functional pool is in the AFD sensory ending (microvilli) membrane. Supporting Evidence: PMID:16415369 GFP-tagged GCY-8, 18, and 23 were localized exclusively to the sensory endings of AFD |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping (cell membrane). Correct but less specific than the AFD sensory-ending localization. Supporting Evidence: PMID:16415369 GFP-tagged GCY-8, 18, and 23 were localized exclusively to the sensory endings of AFD |
| GO:0005929 cilium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to cilium, based on localization to the AFD sensory ending. Reason: The AFD sensory ending comprises a short bona fide cilium plus an elaborate microvillar subcompartment; Nguyen et al. show that the thermosensory guanylyl cyclases are localized to the microvillar compartment (dependent on BBS-8 and DAF-25), whereas the CNG channel is anchored in the proximal cilium. Cilium is therefore an approximation of the true location; retained as non-core. Supporting Evidence: PMID:16415369 GFP-tagged GCY-8, 18, and 23 were localized exclusively to the sensory endings of AFD PMID:25335890 requires BBS-8 and DAF-25 (known as Ankmy2 in mammals) for correct localization of guanylyl cyclases needed for thermosensation |
| GO:0006182 cGMP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: cGMP biosynthesis is the direct process of the cyclase activity, providing cGMP for the TAX-2/TAX-4 channel in AFD. Core. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0007168 receptor guanylyl cyclase signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Receptor guanylyl cyclase signaling pathway (IBA). Pathway-level term appropriate for an AFD rGC feeding cGMP to TAX-4; the activating stimulus (temperature, possibly directly) is not a classical ligand. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0007168 receptor guanylyl cyclase signaling pathway | ISS PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: ISS receptor guanylyl cyclase signaling pathway, same rationale as the IBA. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0009190 cyclic nucleotide biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-derived parent of cGMP biosynthetic process. Correct but less specific. Supporting Evidence: file:worm/gcy-8/gcy-8-uniprot.txt Guanylate cyclase involved in the production of the second messenger cGMP |
| GO:0009266 response to temperature stimulus | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA response to temperature stimulus; correct broad term for an AFD thermosensory rGC. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0009581 detection of external stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA detection of external stimulus; correct but generic parent of detection of temperature stimulus. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0009582 detection of abiotic stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA detection of abiotic stimulus; temperature is an abiotic stimulus, so correct but generic. Supporting Evidence: PMID:16415369 Temperature received by a thermoreceptor is transduced to changes in intracellular cGMP concentration via three guanylyl cyclases, GCY-8, GCY-18, and GCY-23, and transmitted to the TAX-4 CNG channel, resulting in a change of membrane potential of AFD. |
| GO:0016048 detection of temperature stimulus | IMP PMID:21315599 Regulation of response properties and operating range of the... | ACCEPT | Summary: gcy-8 mutant AFD neurons largely fail to respond to oscillating temperature stimuli around the cultivation temperature and have a lowered response threshold (T*AFD); defects rescued by wild-type gcy-8. GCY-8 is required for temperature-evoked AFD activity. Core. Supporting Evidence: PMID:21315599 Together, these results indicate that mutations in gcy-8, but not in gcy-18 and gcy-23, affect the ability of the AFD neurons to respond to oscillating temperature stimuli centered around a mean temperature. PMID:21315599 Interestingly, T*AFD of gcy-8 mutants was also lower than wild-type T*AFD in animals grown at either temperature |
| GO:0031528 microvillus membrane | IDA PMID:27062922 A Glial K/Cl Transporter Controls Neuronal Receptive Ending ... | ACCEPT | Summary: A GFP-tagged gcy-8 fosmid localizes to the AFD microvilli, the receptive ending membrane where thermotransduction occurs. Precise core location. Supporting Evidence: PMID:27062922 GFP fluorescence is localized to AFD microvilli |
| GO:0032528 microvillus organization | IGI PMID:27062922 A Glial K/Cl Transporter Controls Neuronal Receptive Ending ... | ACCEPT | Summary: GCY-8 cyclase activity, inhibited by glial KCC-3-regulated Cl−, sets AFD cGMP levels that antagonize WSP-1-driven actin assembly and thereby control receptive-ending microvillus length. A genuine, experimentally well-supported cGMP-mediated morphological role (secondary to thermotransduction). Supporting Evidence: PMID:27062922 GCY-8, along with PDE-1 and PDE-5, modulate neuron cGMP levels, and cGMP antagonizes WSP-1, which promotes NRE elongation, presumably through actin nucleation. |
| GO:0032528 microvillus organization | IMP PMID:27062922 A Glial K/Cl Transporter Controls Neuronal Receptive Ending ... | ACCEPT | Summary: IMP version: gcy-8 gain- and loss-of-function alleles alter AFD microvilli shape (and gcy-8 loss suppresses kcc-3 defects). Accepted as a secondary function. Supporting Evidence: PMID:27062922 GCY-8, along with PDE-1 and PDE-5, modulate neuron cGMP levels, and cGMP antagonizes WSP-1, which promotes NRE elongation, presumably through actin nucleation. PMID:27062922 Remarkably, however, the gcy-8(tm949) lesion, predicted to eliminate GCY-8 cyclase activity, strongly mitigates the AFD microvilli defects of kcc-3(ok228) mutants |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-derived intracellular signal transduction; correct (cGMP second messenger) but uninformative. Supporting Evidence: file:worm/gcy-8/gcy-8-uniprot.txt Guanylate cyclase involved in the production of the second messenger cGMP |
| GO:0040040 thermosensory behavior | IGI PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: Double/triple gcy mutants are cryophilic or athermotactic, and any single GCY rescues the triple mutant: the three AFD rGCs act redundantly in thermosensory behavior. Core. Supporting Evidence: PMID:16415369 gcy-23 gcy-8 gcy-18 triple mutants show a cryophilic or athermotactic phenotype (no response to temperature) similar to the phenotype of AFD-killed wild-type animals. PMID:16415369 The thermotaxis mutant phenotype of the gcy triple-mutant strain was rescued by expression of any one of the three GCY proteins, suggesting that the GCY-8, -18, and -23 guanylyl cyclases function redundantly |
| GO:0040040 thermosensory behavior | IGI PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: Double/triple gcy mutants are cryophilic or athermotactic, and any single GCY rescues the triple mutant: the three AFD rGCs act redundantly in thermosensory behavior. Core. Supporting Evidence: PMID:16415369 gcy-23 gcy-8 gcy-18 triple mutants show a cryophilic or athermotactic phenotype (no response to temperature) similar to the phenotype of AFD-killed wild-type animals. PMID:16415369 The thermotaxis mutant phenotype of the gcy triple-mutant strain was rescued by expression of any one of the three GCY proteins, suggesting that the GCY-8, -18, and -23 guanylyl cyclases function redundantly |
| GO:0040040 thermosensory behavior | IGI PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: Double/triple gcy mutants are cryophilic or athermotactic, and any single GCY rescues the triple mutant: the three AFD rGCs act redundantly in thermosensory behavior. Core. Supporting Evidence: PMID:16415369 gcy-23 gcy-8 gcy-18 triple mutants show a cryophilic or athermotactic phenotype (no response to temperature) similar to the phenotype of AFD-killed wild-type animals. PMID:16415369 The thermotaxis mutant phenotype of the gcy triple-mutant strain was rescued by expression of any one of the three GCY proteins, suggesting that the GCY-8, -18, and -23 guanylyl cyclases function redundantly |
| GO:0040040 thermosensory behavior | IGI PMID:21315599 Regulation of response properties and operating range of the... | ACCEPT | Summary: Triple gcy mutants are atactic and lack temperature-induced AFD currents (IGI). Core. Supporting Evidence: PMID:21315599 Animals mutant for the TAX-2 and TAX-4 cGMP-gated channels, or triply mutant for the GCY-8, GCY-18 and GCY-23 receptor guanylyl cyclases (rGCs) are atactic, and fail to exhibit temperature-induced currents in the AFD neurons |
| GO:0040040 thermosensory behavior | IMP PMID:21315599 Regulation of response properties and operating range of the... | ACCEPT | Summary: gcy-8 single mutants are defective in executing isothermal tracking; partially rescued by wild-type gcy-8. Core. Supporting Evidence: PMID:21315599 These results indicate that GCY-8 regulates the ability of the AFD neurons to execute IT behavior. |
| GO:0042330 taxis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA taxis; correct parent of the experimentally supported thermotaxis annotation. Supporting Evidence: PMID:16415369 gcy-23 gcy-8 gcy-18 triple mutants show a cryophilic or athermotactic phenotype (no response to temperature) similar to the phenotype of AFD-killed wild-type animals. |
| GO:0043005 neuron projection | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA neuron projection; correct general parent of the AFD sensory ending. Supporting Evidence: PMID:16415369 GFP-tagged GCY-8, 18, and 23 were localized exclusively to the sensory endings of AFD |
| GO:0043052 thermotaxis | IGI PMID:21315599 Regulation of response properties and operating range of the... | ACCEPT | Summary: Genetic interaction data showing the AFD rGCs jointly required for thermotaxis/isothermal tracking. Core. Supporting Evidence: PMID:21315599 Animals mutant for the TAX-2 and TAX-4 cGMP-gated channels, or triply mutant for the GCY-8, GCY-18 and GCY-23 receptor guanylyl cyclases (rGCs) are atactic, and fail to exhibit temperature-induced currents in the AFD neurons PMID:21315599 Thus, while all three rGC genes play roles in regulating the temperature range in which IT behavior can be exhibited, only gcy-8 regulates the ability of the AFD neurons to execute IT behavior. |
| GO:0043052 thermotaxis | IMP PMID:21315599 Regulation of response properties and operating range of the... | ACCEPT | Summary: gcy-8 mutants have isothermal-tracking (thermotaxis) defects with two independent alleles. Core. Supporting Evidence: PMID:21315599 We found that animals carrying two independent alleles of gcy-8 (Figure S2), exhibited significant defects in IT behavior. |
| GO:0044306 neuron projection terminus | IDA PMID:16415369 Identification of guanylyl cyclases that function in thermos... | ACCEPT | Summary: GFP-tagged GCY-8 is localized exclusively to the AFD sensory ending (dendritic terminus). Correct and reasonably specific; microvillus membrane is the more precise compartment. Supporting Evidence: PMID:16415369 GFP-tagged GCY-8, 18, and 23 were localized exclusively to the sensory endings of AFD |
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Download this section (compressed HTML)Q: Are the AFD receptor guanylyl cyclases intrinsically thermosensitive (i.e. the thermoreceptors themselves), and which domain confers temperature dependence of cyclase activity?
Q: Is chloride inhibition via the extracellular S(x)nGPxC motif conserved in GCY-18 and GCY-23, and does extracellular Cl− tune thermosensory operating range in vivo?
Experiment: Express each AFD rGC (GCY-8, GCY-18, GCY-23) alone in a heterologous cell with a cGMP sensor and measure temperature-dependent cGMP production, swapping extracellular and kinase-homology domains to map thermosensitivity.
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