Structure and function of the calcium-selective TRP channel TRPV6

Epithelial calcium channel TRPV6 is a member of the vanilloid subfamily of TRP channels that is permeable to cations and highly selective to Ca2+; it shows constitutive activity regulated negatively by Ca(2+)and positively by phosphoinositol and cholesterol lipids. In this review, we describe the molecular structure of TRPV6 and discuss how its structural elements define its unique functional properties. High Ca(2+)selectivity of TRPV6 originates from the narrow selectivity filter, where Ca(2+)ions are directly coordinated by a ring of anionic aspartate side chains. Divalent cations Ca(2+)and Ba(2+)permeate TRPV6 pore according to the knock-off mechanism, while tight binding of Gd(3+)to the aspartate ring blocks the channel and prevents Na(+)from permeating the pore. The iris-like channel opening is accompanied by an alpha-to-pi helical transition in the pore-lining transmembrane helix S6. As a result of this transition, the intracellular halves of the S6 helices bend and rotate by about 100 deg, exposing different residues to the channel pore in the open and closed states. Channel opening is also associated with changes in occupancy of the transmembrane domain lipid binding sites. The inhibitor 2-aminoethoxydiphenyl borate (2-APB) binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helical bundle and shifts open-closed channel equilibrium towards the closed state by outcompeting lipids critical for activation. Ca(2+)inhibits TRPV6 via binding to calmodulin (CaM), which mediates Ca2+-dependent inactivation. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM C-terminal lobe plugs the channel through a unique cation-pi interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the ion channel pore intracellular entrance. Recent studies of TRPV6 structure and function described in this review advance our understanding of the role of this channel in physiology and pathophysiology and inform new therapeutic design.

Automated summary

This review discusses the molecular structure of the epithelial calcium channel TRPV6, highlighting its unique functional properties such as high Ca2+ selectivity and channel opening mechanism. The inhibitor 2-aminoethoxydiphenyl borate (2-APB) and calmodulin (CaM) play important roles in regulating TRPV6 activity.