title: Behind the curtain: cellular mechanisms for allosteric modulation of calcium-sensing receptors.
abstract: Calcium-sensing receptors (CaSR) are integral to regulation of systemic Ca(2+) homeostasis. Altered expression levels or mutations in CaSR cause Ca(2+) handling diseases. CaSR is regulated by both endogenous allosteric modulators and allosteric drugs, including the first Food and Drug Administration-approved allosteric agonist, Cinacalcet HCl (Sensipar®). Recent studies suggest that allosteric modulators not only alter function of plasma membrane-localized CaSR, but regulate CaSR stability at the endoplasmic reticulum. This brief review summarizes our current understanding of the role of membrane-permeant allosteric agonists in cotranslational stabilization of CaSR, and highlights additional, indirect, signalling-dependent role(s) for membrane-impermeant allosteric drugs. Overall, these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function, and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to CaSR abundance and signalling.
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, PA, USACancer Drug Research Laboratory, McGill University/Royal Victoria Hospital, Montreal, QC, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Cavanaugh
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, PA, USACancer Drug Research Laboratory, McGill University/Royal Victoria Hospital, Montreal, QC, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, PA, USACancer Drug Research Laboratory, McGill University/Royal Victoria Hospital, Montreal, QC, Canada.
authors.forename: Gerda E
authors.initials: GE
authors.lastname: Breitwieser
mesh_terms: D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044169:Receptors, Calcium-Sensing