TRPV5 in renal tubular calcium handling and its potential relevance for nephrolithiasis

Abstract Nephrolithiasis or renal stone disease is an increasingly common problem, and its relatively high recurrence rate demands for better treatment options. The majority of patients with nephrolithiasis have calcium (Ca 2+ )-containing stones, which develop upon "supersaturation" of the urine with insoluble Ca 2+ salts. Hence, processes that influence the delivery and renal handling of Ca 2+ may influence stone formation. Idiopathic hypercalciuria is indeed frequently observed in patients with Ca 2+ -containing kidney stones. Genetic screens of nephrolithiasis determinants have identified an increasing number of gene candidates, most of which are involved in renal Ca 2+ handling. This review provides an outline of the current knowledge regarding genetics of nephrolithiasis, and will mainly focus on the epithelial Ca 2+ channel TRPV5 (transient receptor potential vanilloid 5), an important player in Ca 2+ homeostasis. Being a member of the TRP family of ion channels, TRPV5 is currently part of a revolution in structural biology. Recent technological breakthroughs in the cryo-electron microscopy field, combined with improvements in biochemical sample preparation, have resulted in high-resolution three-dimensional structural models of integral membrane proteins, including TRPV5. These models are currently being used to explore the proteins' structure-function relationship, elucidate the molecular mechanisms of channel regulation, and study the putative effects of disease variants. Combined with other multidisciplinary approaches, this may open the avenue towards better understanding of the pathophysiological mechanisms involved in hypercalciuria and stone formation, and it may ultimately facilitate prevention of stone recurrence by development of effective drugs.