Akinesia and freezing caused by Na(+) leak-current channel (NALCN) deficiency corrected by pharmacological inhibition of K(+) channels and gap junctions.

Abstract

The Na(+) leak-current channel (NALCN) regulates locomotion, respiration, and intellectual development. Previous work highlighted striking similarities between characteristic movement phenotypes of NALCN-deficient animals (Drosophila and Caenorhabditis elegans) and the major symptoms of Parkinson's disease and primary progressive freezing gait. We have discovered novel physiological connections between the NALCN, K(+) channels, and gap junctions that mediate regulation of locomotion in C. elegans. Drugs that block K(+) channels and gap junctions or that activate Ca(++) channels significantly improve movement of NALCN-deficient animals. Loss-of-function of the NALCN creates an imbalance in ions, including K(+) and Ca(++) , that interferes with normal cycles of depolarization-repolarization. This work suggests new therapeutic strategies for certain human movement disorders. J. Comp. Neurol. 525:1109-1121, 2017. © 2016 Wiley Periodicals, Inc.