Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis

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@article{a00d92abf81841669bf0ae026b715361,
title = "Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis",
abstract = "The calcium-sensing receptor (CaSR) is a class C G-protein coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CaSR utilises multiple heterotrimeric G-proteins to mediate signalling effects including: activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CaSR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CaSR signalling and trafficking mechanisms. The first, identified by studying a CaSR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CaSR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CaSR internalisation and reduce multiple CaSR-mediated signalling pathways. Furthermore, these studies showed that the CaSR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11pathway. Thus, studies of FHH and ADH associated mutations have revealed novel steps by which CaSR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.",
keywords = "Journal Article",
author = "Caroline Gorvin",
year = "2018",
month = mar,
day = "29",
doi = "10.1530/JME-18-0049",
language = "English",
journal = "Journal of Molecular Endocrinology",
issn = "0952-5041",
publisher = "BioScientifica",

}

RIS

TY - JOUR

T1 - Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis

AU - Gorvin, Caroline

PY - 2018/3/29

Y1 - 2018/3/29

N2 - The calcium-sensing receptor (CaSR) is a class C G-protein coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CaSR utilises multiple heterotrimeric G-proteins to mediate signalling effects including: activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CaSR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CaSR signalling and trafficking mechanisms. The first, identified by studying a CaSR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CaSR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CaSR internalisation and reduce multiple CaSR-mediated signalling pathways. Furthermore, these studies showed that the CaSR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11pathway. Thus, studies of FHH and ADH associated mutations have revealed novel steps by which CaSR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.

AB - The calcium-sensing receptor (CaSR) is a class C G-protein coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CaSR utilises multiple heterotrimeric G-proteins to mediate signalling effects including: activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CaSR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CaSR signalling and trafficking mechanisms. The first, identified by studying a CaSR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CaSR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CaSR internalisation and reduce multiple CaSR-mediated signalling pathways. Furthermore, these studies showed that the CaSR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11pathway. Thus, studies of FHH and ADH associated mutations have revealed novel steps by which CaSR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.

KW - Journal Article

U2 - 10.1530/JME-18-0049

DO - 10.1530/JME-18-0049

M3 - Review article

C2 - 29599414

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

ER -