TRPV5: an ingeniously controlled calcium channel

Body Ca2+ homeostasis is tightly controlled and slight disturbances in renal Ca2+ reabsorption can lead to excessive urine Ca2+ excretion and promote kidney stone formation. The epithelial Ca2+ channel TRPV5 constitutes the rate-limiting step of active Ca2+ reabsorption in the kidney. Elucidation of the molecular pathways controlling TRPV5 function provides important information for our understanding of renal Ca2+ handling, since active Ca2+ reabsorption fine-tunes the final amount of Ca2+ excreted into the urine. Over the last years, the molecular regulation of TRPV5 has been dismantled in detail. Various calciotropic hormones, known to alter renal Ca2+ reabsorption, affect the expression of TRPV5. Others stimulate the trafficking of TRPV5 to the plasma membrane, while a number of associated proteins and ions control channel activity at the plasma membrane. Dynamic cell surface presence of TRPV5 is largely mediated by endosomal recycling processes allowing internalized channels to reappear at the plasma membrane. We present recently identified factors shown to modulate TRPV5 activity by diverse mechanisms to ultimately control renal Ca2+ handling. The selected factors include klotho, tissue kallikrein, pH, Ca2+, Mg2+, PIP2 and WNK4. This review covers the distinctive properties and regulation of the highly Ca2+-selective TRPV5 channel and highlights the implications for our understanding of the process of Ca2+ reabsorption.