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Calcium-sensing receptor signaling - How human disease informs biology.

ABSTRACT: The calcium-sensing receptor (CaSR) is a class C G-protein-coupled receptor (GPCR) that plays a fundamental role in extracellular calcium homeostasis by regulating parathyroid hormone (PTH) release. Although the CaSR was identified over 25 years ago, new mechanistic details of how the CaSR controls PTH secretion have recently been uncovered demonstrating heteromerization and phosphate binding affect CaSR-mediated suppression of PTH release. In addition, understanding of how the CaSR performs diverse functions in different cellular contexts is just beginning to be elucidated, with new evidence of tissue-specific regulation, and endo-somal signaling. Insights into CaSR activation mechanisms and signaling bias have arisen from studies of CaSR mutations, which cause disorders of calcium homeostasis. Functional assessment of these mutations demonstrated the importance of the homodimer interface and transmembrane domain in biased signaling and showed CaSR mutations can facilitate G-protein-independent signaling. Population genetics studies have allowed a greater understanding of the prevalence of calcemic disorders and revealed new pathophysiological roles.

SUBMITTER: Gorvin CM

PROVIDER: S-EPMC7611003 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Calcium-sensing receptor signaling - How human disease informs biology.

Gorvin Caroline M CM

Current opinion in endocrine and metabolic research 20200702

The calcium-sensing receptor (CaSR) is a class C G-protein-coupled receptor (GPCR) that plays a fundamental role in extracellular calcium homeostasis by regulating parathyroid hormone (PTH) release. Although the CaSR was identified over 25 years ago, new mechanistic details of how the CaSR controls PTH secretion have recently been uncovered demonstrating heteromerization and phosphate binding affect CaSR-mediated suppression of PTH release. In addition, understanding of how the CaSR performs div ...[more]

PMID: 34141952

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Project description:BackgroundNerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.Methodology/principal findingsBy combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Conclusions/significanceOur experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability.

Dataset Information

Calcium-sensing receptor signaling - How human disease informs biology.

Publications

Calcium-sensing receptor signaling - How human disease informs biology.

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