Abstract 18586: GPD1-L Inhibits the Cardiac Sodium Channel Nav1.5 by decreasing SIRTUIN1 Activity
GPD1-L is a cytosolic protein that catalyzes the reduction of dihydroxyacetone phosphate + NADH into glycerol 3-phosphate + NAD+. Mutations in GPD1-L have been linked to Brugada syndrome and sudden infant death syndrome. GPD1-L regulates the cardiac Na+ channel Nav1.5 but the mechanism is not fully understood. We have recently shown that SIRTUIN1 (SIRT1), a NAD+ dependent deacetylase, increases Na+ current (INa) by deacetylating Nav1.5 and increasing cell surface expression. We therefore tested the hypothesis that GPD1-L mutations alter Nav1.5 activity and INa through a SIRT1-dependent mechanism, and that GPD1L’s catalytic function is an essential component of this regulation. Whole cell patch clamp studies in HEK cells demonstrated that a decrease of GPD1-L expression by siRNA knockdown or catalytic function by mutagenesis increases INa, while overexpression of the A280V Brugada syndrome GPD1-L mutation decreased INa. Moreover, catalytic deficient GPD1-L increased and A280V GPD1-L decreased cell surface expression of Nav1.5. Co-immunoprecipitation studies showed that GPD1-L binds to SIRT1 (Figure A). In addition, catalytically inactive GPD1-L increased and A280V GPD1-L decreased SIRT1deacetylase activity (Figure B). In summary, our evidence supports the hypothesis that GPD1-L functions as a negative regulator of the cardiac Na channel Nav1.5 by interacting with SIRT1 and diminishing its activity; the A280V GPD1-L mutation enhances that inhibition, leading to Brugada syndrome.
- © 2013 by American Heart Association, Inc.