Functional basis for calmodulation of the TRPV5 calcium channel.

transport in the kidney. Abstract figure legend Calmodulation of the epithelial calcium channel TRPV5. The Ca2 concentration modulates calmodulin-dependent inhibition of TRPV5. The three panels depict key moments in a continuum of increasing Ca2 concentration (gradient slider under the panels). The left panel shows a situation where Ca2 is virtually absent and CaM is in its apo-CaM conformation. The interaction between TRPV5 and apo-CaM does not rely on the presence of Ca2 even though CaMdependent inhibition of TRPV5 is compromised. The middle panel depicts a physiologically-relevant Ca2 concentration where one or both lobes of CaM are calcified and the TRPV5-CaM complex undergoes a conformational change that plugs the TRPV5 pore and inhibits the channel. The rightmost panel shows that increased intracellular Ca2 concentration stimulates the recruitment of multiple CaM molecules to active TRPV5 channels, leading to flexible binding stoichiometry. Through this mechanism CaM is able to effectively close TRPV5 channels based on the intracellular Ca2 concentration, preventing levels of Ca2 entry that could lead to cytotoxicity. This article is protected by copyright. All rights reserved.