Temperature sensing by the calcium-sensing receptor

Sarah C Brennan; Hee-Chang Mun; Leigh Delbridge; Philip W Kuchel; Arthur D Conigrave

doi:10.3389/fphys.2023.1117352

Temperature sensing by the calcium-sensing receptor

Front Physiol. 2023 Feb 2:14:1117352. doi: 10.3389/fphys.2023.1117352. eCollection 2023.

Authors

Sarah C Brennan^{1

2}, Hee-Chang Mun², Leigh Delbridge³, Philip W Kuchel¹, Arthur D Conigrave^{1

2}

Affiliations

¹ School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.
² Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
³ Department of Surgery, Mater Hospital, North Sydney, NSW, Australia.

Abstract

Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Introduction: Extracellular Ca²⁺ concentration (Ca²⁺ _o) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca²⁺ _o-sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures. Methods: Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells. Results: We found that the frequency of Ca²⁺ _o-induced Ca²⁺ _i oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor's C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation. Discussion and Conclusion: CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.

Keywords: GPCR; calcium sensing receptor; intracellular calcium oscillations; protein kinase C; protein phosphatase; temperature sensing.