Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli
Thermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, incl...
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eLife Sciences Publications Ltd
2025-04-01
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| Online Access: | https://elifesciences.org/articles/103497 |
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| author | Martina Rudgalvyte Zehan Hu Dieter Kressler Jörn Dengjel Dominique A Glauser |
| author_facet | Martina Rudgalvyte Zehan Hu Dieter Kressler Jörn Dengjel Dominique A Glauser |
| author_sort | Martina Rudgalvyte |
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| description | Thermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems. |
| format | Article |
| id | doaj-art-5541280c16104367b9a18fc4706e44bf |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-5541280c16104367b9a18fc4706e44bf2025-08-20T02:55:44ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011410.7554/eLife.103497Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuliMartina Rudgalvyte0https://orcid.org/0009-0003-6201-6200Zehan Hu1Dieter Kressler2https://orcid.org/0000-0003-4855-3563Jörn Dengjel3https://orcid.org/0000-0002-9453-4614Dominique A Glauser4https://orcid.org/0000-0002-3228-7304Department of Biology, University of Fribourg, Fribourg, SwitzerlandDepartment of Biology, University of Fribourg, Fribourg, SwitzerlandDepartment of Biology, University of Fribourg, Fribourg, Switzerland; Metabolomics and Proteomics Platform (MAPP), Department of Biology, University of Fribourg, Fribourg, SwitzerlandDepartment of Biology, University of Fribourg, Fribourg, SwitzerlandDepartment of Biology, University of Fribourg, Fribourg, SwitzerlandThermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems.https://elifesciences.org/articles/103497behavioral plasticitypainkinase substratesCaM kinasecalcineurin |
| spellingShingle | Martina Rudgalvyte Zehan Hu Dieter Kressler Jörn Dengjel Dominique A Glauser Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli eLife behavioral plasticity pain kinase substrates CaM kinase calcineurin |
| title | Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| title_full | Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| title_fullStr | Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| title_full_unstemmed | Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| title_short | Antagonist actions of CMK-1/CaMKI and TAX-6/calcineurin along the C. elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| title_sort | antagonist actions of cmk 1 camki and tax 6 calcineurin along the c elegans thermal avoidance circuit orchestrate adaptation of nociceptive response to repeated stimuli |
| topic | behavioral plasticity pain kinase substrates CaM kinase calcineurin |
| url | https://elifesciences.org/articles/103497 |
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