What structures did, and did not, reveal about the function of the epithelial Ca²⁺ channels TRPV5 and TRPV6

Transient Receptor Potential Vanilloid 5 and 6 (TRPV5 and TRPV6) are Ca²⁺ selective epithelial ion channels. They are the products of a relatively recent gene duplication in mammals, and have high sequence homology to each other. Their functional properties are also much more similar to each other than to other members of the TRPV subfamily. They are both constitutively active, and this activity depends on the endogenous cofactor phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]. Both channels undergo Ca²⁺-induced inactivation, which is mediated by direct binding of the ubiquitous Ca²⁺ binding protein calmodulin (CaM) to the channels, and by a decrease in PI(4,5)P₂ levels by Ca²⁺ -induced activation of phospholipase C (PLC). Recent cryo electron microscopy (cryo-EM) and X-ray crystallography structures provided detailed structural information for both TRPV5 and TRPV6. This review will discuss this structural information in the context of the function of these channels focusing on the mechanism of CaM inhibition, activation by PI(4,5)P₂ and binding of pharmacological modulators.