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Temperature sensing by the calcium-sensing receptor

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.

 

Comments：

The study described in the introduction suggests that calcium-sensing receptors (CaSRs), a type of G protein-coupled receptor (GPCR), may be involved in temperature sensing. The researchers used CaSR-expressing HEK-293 cells to test whether CaSR-dependent signaling is temperature-sensitive. They found that the frequency of Ca2+ o-induced Ca2+ i oscillations was linearly dependent on temperature in a pathophysiologically relevant range, but not the integrated response.

Chimeric receptor analysis revealed that the C-terminus of the receptor is required for temperature-dependent modulation, and experiments with CaSR mutants and a PKC inhibitor suggested that repetitive phosphorylation and dephosphorylation are important for this mechanism. These findings suggest that GPCRs, including CaSRs, may contribute to temperature sensing more generally.

It should be noted that the understanding of the role of GPCRs in temperature sensing is still limited and further research is needed to fully elucidate the mechanisms involved.

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S7208 Bisindolylmaleimide I (GF109203X) Bisindolylmaleimide I (GF109203X, GO 6850) is a potent PKC inhibitor with IC50 of 20 nM, 17 nM, 16 nM, and 20 nM for PKCα, PKCβI, PKCβII, and PKCγ in cell-free assays, respectively, showing more than 3000-fold selectivity for PKC as compared to EGFR, PDGFR and insulin receptor.

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PKC