Insight into the hormonal regulation of the epithelial calcium channels TRPV5 & TRPV6

Abstract

Ca2+ plays a fundamental role in many cellular processes and its extracellular concentration is kept under strict control by the concerted actions of kidney, intestine and bone to allow proper physiological functions. The first step in active, transcellular Ca2+ transport is the influx of Ca2+ across the apical plasma membrane. Inside the cell, Ca2+ is bound to specialized proteins, called calbindins, to maintain low intracellular Ca2+ concentrations. Bound Ca2+ subsequently diffuses to the basolateral side of the cell, where it is extruded into the bloodstream via the Na+/Ca2+-exchanger (NCX1) and/or plasma membrane Ca2+-ATPase (PMCA1b). The epithelial Ca2+ channels TRPV5 and TRPV6 represent a new family of Ca2+ channels, which belong to the superfamily of transient receptor potential channels, and constitute the apical Ca2+ entry mechanism in active Ca2+ transport in kidney and intestine. The central role of TRPV5 and TRPV6 in active Ca2+ (re)absorption makes it a prime target for regulation to maintain Ca2+ balance. Therefore, the aim of this thesis was to investigate the hormonal regulation of the Ca2+ transport proteins, in particular TRPV5 and TRPV6, and provide insight into the physiological role of these Ca2+ channels and the molecular nature of Ca2+ homeostasis.