Structure and function of the calcium-selective TRP channel TRPV6

Area of Science:

• Molecular Biology
• Ion Channel Physiology
• Structural Biology

Background:

• Epithelial calcium channel TRPV6 is a highly Ca²⁺-selective ion channel.
• TRPV6 activity is regulated by intracellular Ca²⁺, lipids, and specific inhibitors.
• Understanding TRPV6 structure-function relationships is key to its physiological and pathological roles.

Purpose of the Study:

• To review the molecular structure of TRPV6 and its correlation with functional properties.
• To discuss the mechanisms of ion permeation, channel gating, and regulation by inhibitors and Ca²⁺-binding proteins.

Main Methods:

• Structural analysis of TRPV6, focusing on the selectivity filter and pore-lining helices.
• Investigation of ion permeation mechanisms (knock-off, block by Gd³⁺).
• Characterization of inhibitor binding (2-APB) and Ca²⁺-dependent inactivation via calmodulin (CaM).

Main Results:

• TRPV6's narrow selectivity filter with aspartate residues ensures high Ca²⁺ selectivity.
• Channel opening involves an α-to-π helical transition in S6, altering the pore and lipid binding sites.
• 2-APB inhibits TRPV6 by binding to a transmembrane pocket, while CaM binding to the pore entrance mediates Ca²⁺-dependent inactivation.

Conclusions:

• TRPV6 structure dictates its unique Ca²⁺ selectivity and gating mechanisms.
• Modulation by lipids, 2-APB, and CaM highlights its complex regulation.
• Insights into TRPV6 structure-function advance understanding and inform therapeutic strategies for diseases involving calcium homeostasis.