Molecular partners of the TRPV5 channel: an odyssey into the regulation of epithelial Ca2+ transport.

Abstract

Many physiological functions rely on the exact maintenance of body Ca2+ balance. Therefore, the extracellular Ca2+ concentration is kept under strict control by the concerted action of intestine, bone and kidney. Ca2+ can pass through epithelial tissues and then, reach the blood compartment via passive paracellular and active transcellular Ca2+ transport. The latter allows the body to regulate Ca2+ transport independently of the Na+ balance and to respond immediately to fluctuations of nutritional Ca2+. The rate-limiting step of Ca2+ influx in active Ca2+ (re)absorption is the epithelial Ca2+ channel, Transient Receptor Potential Vanilloïd 5 (TRPV5). TRPV5 physiological role has been substantiated by several mouse models of Ca2+-related disorders implying that a tight channel regulation is of vital importance. The aim of this thesis was, therefore, to discover the partner proteins that determine Ca2+ influx through TRPV5 channel and to elucidate their functional role. In this respect, four proteins were identified by microarrays analysis: the protein kinase C substrate 80K-H, the FK506-binding protein (FKBP) 52, the serine protease tissue kallikrein (TK) and the Ca2+-binding protein calbindin-D28K. The characterization of these proteins provided insight into our understanding of channel physiology by demonstrating how partner proteins modulate TRPV5 activity and adjust accordingly the amount of Ca2+ entering into the renal epithelial cell.