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.