Rohacs T, Fluck EC, De Jesús-Pérez JJ, Moiseenkova-Bell VY. Cell Calcium. 2022 Sep;106:102620. doi: 10.1016/j.ceca.2022.102620. Epub 2022 Jul 3.
Abstract
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.
Conclusions
The last 6 years brought a remarkable progress in our understanding of the structural basis of the physiological regulation and pharmacology of the epithelial Ca2+ channels TRPV5 and TRPV6. The overall architectures of these channels determined by three different laboratories, are very similar to each other, and also similar to other channels in the TRPV family. There is also a clear agreement in the molecular mechanism of channel inhibition by the endogenous protein modulator CaM, three structures from three laboratories showing essentially the same binding mode and pore block in both TRPV5 and TRPV6. The structures determined so far show less agreement on how pharmacological small molecule inhibitors and the endogenous ligand PI(4,5)P2 bind to and activate these channels. Future work with higher resolution structures will likely shed light to whether these discrepancies reflect inherent differences between these channels, or caused by differences in experimental conditions between different laboratories.