@misc{10481/107652,
year = {2025},
month = {10},
url = {https://hdl.handle.net/10481/107652},
abstract = {The small-conductance calcium-activated potassium channel SK3, encoded by
the KCNN3 gene, plays a critical role in regulating dopaminergic neuron (DN) firing
patterns by modulating after hyperpolarization currents. SK3 dysfunction has been
implicated in neuropsychiatric and neurodegenerative disorders. We analyzed structural
and functional consequences of KCNN3 splicing and genetic variation. Alternative
splicing variants of the KCNN3 gene were retrieved from the Ensembl database
and aligned using T-Coffee, manually inspected and curated. Protein domains
were identified with Pfam 35.0, SMART 9.0, and InterPro 98.0, and visualized. An
AlphaFold2 model of SK3 full-length protein (UniProt: Q9UGI6) used as reference and
structural models of its splicing variants were predicted with ColabFold. Functional
domains (S1–S6 transmembrane helices, H5 pore loop, and calmodulin-binding)
were defined and superimposed onto the AlphaFold2 reference. Domain integrity
was assessed based on completeness of all expected residue indices within each
functional region. SNPs and CNVs across all coding KCNN3 splicing variants were
analyzed, classified, and filtered to isolate pathogenic variants prioritizing nonsynonymous amino acid substitutions. Differential variant impacts across splicing
isoforms were assessed by mapping variant positions to individual transcript protein
sequences and used to predict functional consequences. Two long and two short
splicing variants are known. Short variants lack the motif required for potassium
channels. Pathogenic variants result from missense mutations resulting in amino
acid substitutions. In all cases, the consequential effects depend on the specific
location and role of the amino acid being changed.},
organization = {National Institutes of Health (NIH) – (U19AG076581, P30AG066546)},
organization = {Spanish Ministry of Science and Technology – (RTI2018-098983-B-100)},
publisher = {Frontiers Media},
keywords = {SK3 channels},
keywords = {Neurons},
keywords = {dopaminergic neurons},
title = {In silico prediction of the impact of genomic variations in the small conductance calcium activated potassium channel SK3 structure and function},
doi = {10.3389/fnins.2025.1631536},
author = {Padilla, Lucía and Val Muñoz, María Coral Del and Neidre, Daria B. and Kokenge, Agustín S. and Martinez, Juan E. and Teixeira, Antonio L. and Zwir Nawrocki, Jorge Sergio Igor and de Erausquin, Gabriel},
}