title: Regulation of stability and trafficking of calcium-sensing receptors by pharmacologic chaperones.
abstract: Gain- or loss-of-function mutations and polymorphisms of the calcium-sensing receptor (CaSR) cause Ca(2+) handling diseases. Altered expression and/or signaling of wild-type CaSR can also contribute to pathology. Recent studies have demonstrated that a significant proportion of mutations cause altered targeting and/or trafficking of CaSR to the plasma membrane. Pharmacological approaches to rescue of CaSR function include treatment with allosteric modulators, which potentiate the effects of the orthosteric agonist Ca(2+). Dissection of the mechanism(s) contributing to allosteric agonist-mediated rescue of loss-of-function CaSR mutants has demonstrated pharmacologic chaperone actions coincident with CaSR biosynthesis. The distinctive responses to the allosteric agonist (NPS R-568), which promotes CaSR stability, and the allosteric antagonist (NPS 2143), which promotes CaSR degradation, have led to a model for a conformational checkpoint during CaSR biosynthesis. The conformational checkpoint would "tune" CaSR biosynthesis to cellular signaling state. Navigation of a distinct checkpoint for endoplasmic release can also be augmented by pharmacologic chaperones. The diverse, post-endoplasmic reticulum quality control site(s) for pharmacologic chaperone modulation of CaSR stability and trafficking redefines the role(s) of allosteric modulators in regulation of overall GPCR function.
authors: Cancer Drug Research Laboratory, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors: Ying
authors: Y
authors: Huang
authors: Alice
authors: A
authors: Cavanaugh
authors: Gerda E
authors: GE
authors: Breitwieser
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004194:Disease; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D044169:Receptors, Calcium-Sensing; D002118:Calcium