A cooperative knock-on mechanism underpins Ca2+-selective cation permeation in TRPV channels.
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
01 05 2023
01 05 2023
Historique:
received:
25
07
2022
revised:
15
11
2022
accepted:
28
02
2023
entrez:
21
3
2023
pubmed:
22
3
2023
medline:
24
3
2023
Statut:
ppublish
Résumé
The selective exchange of ions across cellular membranes is a vital biological process. Ca2+-mediated signaling is implicated in a broad array of physiological processes in cells, while elevated intracellular concentrations of Ca2+ are cytotoxic. Due to the significance of this cation, strict Ca2+ concentration gradients are maintained across the plasma and organelle membranes. Therefore, Ca2+ signaling relies on permeation through selective ion channels that control the flux of Ca2+ ions. A key family of Ca2+-permeable membrane channels is the polymodal signal-detecting transient receptor potential (TRP) ion channels. TRP channels are activated by a wide variety of cues including temperature, small molecules, transmembrane voltage, and mechanical stimuli. While most members of this family permeate a broad range of cations non-selectively, TRPV5 and TRPV6 are unique due to their strong Ca2+ selectivity. Here, we address the question of how some members of the TRPV subfamily show a high degree of Ca2+ selectivity while others conduct a wider spectrum of cations. We present results from all-atom molecular dynamics simulations of ion permeation through two Ca2+-selective and two non-selective TRPV channels. Using a new method to quantify permeation cooperativity based on mutual information, we show that Ca2+-selective TRPV channel permeation occurs by a three-binding site knock-on mechanism, whereas a two-binding site knock-on mechanism is observed in non-selective TRPV channels. Each of the ion binding sites involved displayed greater affinity for Ca2+ over Na+. As such, our results suggest that coupling to an extra binding site in the Ca2+-selective TRPV channels underpins their increased selectivity for Ca2+ over Na+ ions. Furthermore, analysis of all available TRPV channel structures shows that the selectivity filter entrance region is wider for the non-selective TRPV channels, slightly destabilizing ion binding at this site, which is likely to underlie mechanistic decoupling.
Identifiants
pubmed: 36943243
pii: 213957
doi: 10.1085/jgp.202213226
pmc: PMC10038842
pii:
doi:
Substances chimiques
Calcium
SY7Q814VUP
TRPV Cation Channels
0
Cations
0
Transient Receptor Potential Channels
0
Sodium
9NEZ333N27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/N013735/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M010996/1
Pays : United Kingdom
Informations de copyright
© 2023 Ives et al.
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