Calcium binding and permeation in TRPV channels: Insights from molecular dynamics simulations

Abstract

Some calcium channels selectively permeate Ca2+, despite the high concentration of monovalent ions in the surrounding environment, which is essential for many physiological processes. Without atomistic and dynamical ion permeation details, the underlying mechanism of Ca2+ selectivity has long been an intensively studied, yet controversial, topic. This study takes advantage of the homologous Ca2+-selective TRPV6 and non-selective TRPV1 and utilizes the recently solved open-state structures and a newly developed multisite calcium model to investigate the ion binding and permeation features in TRPV channels by molecular dynamics simulations. Our results revealed that the open-state TRPV6 and TRPV1 show distinct ion binding patterns in the selectivity filter, which lead to different ion permeation features. Two Ca2+ ions simultaneously bind to the selectivity filter of TRPV6 compared with only one Ca2+ in the case of TRPV1. Multiple Ca2+ binding at the selectivity filter of TRPV6 permeated in a concerted manner, which could efficiently block the permeation of Na+. Cations of various valences differentiate between the binding sites at the entrance of the selectivity filter in TRPV6. Ca2+ preferentially binds to the central site with a higher probability of permeation, repelling Na+ to a peripheral site. Therefore, we believe that ion binding competition at the selectivity filter of calcium channels, including the binding strength and number of binding sites, determines Ca2+ selectivity under physiological conditions.

Recent advances on the structure and the function relationships of the TRPV4 ion channel

“…The first four have a lower selectivity for cations with a permeability ratio of PCa/PNa ~1–10; furthermore, they are responsive to physical and chemical stimuli and play a significant role in thermosensation, chemosensation, and nociception [ 7 ]. On the other hand, TRPV5 and TRPV6 channels are highly selective to Ca 2+ (PCa 2+ /PNa + >100) and participate in regulating Ca 2+ homeostasis in the kidneys and intestines [ 22 ].…”