Identification of novel functional sites in the Ca_v1.3 calcium channel α1-subunit using evolutionary modeling.

Authors

Xuechen Tang, Horia C Hermenean, Alesia Yakimchyk, Petronel Tuluc, Nadine J Ortner, Klaus R Liedl

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 32. Pages e2602636123. Aug 11, 2026. Epub Aug 03, 2026.

Abstract

Voltage-gated calcium channels (VGCCs) regulate differentiation, function, and survival of excitable cells, and pathogenic variants cause diverse disorders. Most known disease-associated VGCC mutations affect well-characterized regions controlling voltage-dependent gating and channel kinetics, while many residues remain functionally unannotated. We developed an evolutionary model to predict the pathogenic potential of residues in the pore-forming Ca_v1.3 subunit, previously validated with de novo gain-of-function variants linked to neurodevelopmental diseases. Here we show that the model recapitulates established functional regions and prospectively identifies functional sites at single-amino acid resolution. Electrophysiological analyses of five predicted variants across multiple channel domains confirmed functional alterations. The approach also captures loss-of-function variants typically pathogenic only in the homozygous state, establishing a predictive framework for identifying and functionally characterizing pathogenic variants in Ca_v1.3 and related ion channels.

PMID:
42546191
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.