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

•TRPV5 and TRPV6 are Ca2+ selective epithelial ion channels.•Molecular details of TRPV5 and TRPV6 channels gating.•TRPV5 and TRPV6 structural pharmacology. Transient Receptor Potential Vanilloid 5 and 6 (TRPV5 and TRPV6) are Ca2+ selective epithelial ion channels. They are the products of a relative...

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Published in:Cell calcium (Edinburgh) 2022-09, Vol.106, p.102620-102620, Article 102620
Main Authors: Rohacs, Tibor, Fluck, Edwin C., De Jesús-Pérez, José J., Moiseenkova-Bell, Vera Y.
Format: Article
Language:English
Subjects:
Cryo electron microscopy
Structure-based drug design
TRPV5 channel
TRPV6 channel
X ray crystallography
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Summary:•TRPV5 and TRPV6 are Ca2+ selective epithelial ion channels.•Molecular details of TRPV5 and TRPV6 channels gating.•TRPV5 and TRPV6 structural pharmacology. 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. [Display omitted]
ISSN:0143-4160
1532-1991
DOI:10.1016/j.ceca.2022.102620