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 Ca2+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 Ca2+selectivity of TRPV6 originates from the narrow selectivity filter, where Ca2+ions are directly coordinated by a ring of anionic aspartate side chains. Divalent cations Ca2+and Ba2+permeate TRPV6 pore according to the knock‐off mechanism, while tight binding of Gd3+to the aspartate ring blocks the channel and prevents Na+from permeating the pore. The iris‐like channel opening is accompanied by an α‐to‐π 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. Ca2+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‐π 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.
Zn2+, Mg2+and Ca2+are essential divalent cations implicated in many metabolic processes and signalling pathways. An emerging new paradigm is that the organismal balance of these cations predominantly depends on a common gatekeeper, the channel-kinase TRPM7. Despite extensive electrophysiological studies and recent cryo-EM analysis, an open question is how the channel activity of TRPM7 is activated. Here, we performed site-directed mutagenesis of mouse TRPM7 in conjunction with patch-clamp assessment of whole-cell and single-channel activity and molecular dynamics (MD) simulations to show that the side chains of conserved N1097 form an inter-subunit Mg2+regulatory site located in the lower channel gate of TRPM7. Our results suggest that intracellular Mg2+binds to this site and stabilizes the TRPM7 channel in the closed state, whereas the removal of Mg2+favours the opening of TRPM7. Hence, our study identifies the structural underpinnings through which the TRPM7 channel is controlled by cytosolic Mg2+, representing a new structure–function relationship not yet explored among TRPM channels.
more » « less- NSF-PAR ID:
- 10367835
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Cellular and Molecular Life Sciences
- Volume:
- 79
- Issue:
- 5
- ISSN:
- 1420-682X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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