title: The role of the calcium sensing receptor in regulating intracellular calcium handling in human epidermal keratinocytes.
abstract: Calcium is critical for controlling the balance of proliferation and differentiation in epidermal keratinocytes. We previously reported that the calcium sensing receptor (CaR) is required for mediating Ca2+ signaling and extracellular Ca2+ (Ca2+(o))-induced differentiation. In this study, we investigated the mechanism by which CaR regulates intracellular Ca2+ (Ca2+(i)) and its role in differentiation. Membrane fractionation, fluorescence immunolocalization, and co-immunoprecipitation studies were performed to assess potential interactions between CaR and other regulators of Ca2+ stores and channels. We found that the glycosylated form of CaR forms a complex with phospholipase C gamma1, IP3 receptor (IP3R), and the Golgi Ca2+-ATPase, secretory pathway Ca2+-ATPase 1, in the trans-Golgi. Inactivation of the endogenous CaR gene by adenoviral expression of a CaR antisense cDNA inhibited Ca2+(i) response to Ca2+(o), decreased Ca2+(i) stores, decreased Ca2+(o)-induced differentiation, but augmented store-operated channel activity and Ca2+ uptake by intracellular organelles. Our results indicate that CaR regulates keratinocyte differentiation in part by modulating Ca2+(i) stores via interactions with Ca2+ pumps and channels that regulate those stores.
authors.affiliation: Endocrine Unit, Department of Medicine, Veteran Affairs Medical Center and University of California, San Francisco, California 94121, USA. chia-ling.tu@uscsf.edu
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Tu
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000201:enzymology / Q000502:physiology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051966:Phospholipase C gamma / Q000502:physiology; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D044169:Receptors, Calcium-Sensing; D051966:Phospholipase C gamma; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium