Abstract 15380: Cardiac Conduction Disease associated with Attenuated TRPM4 Channel Endocytosis
We have previously shown that cardiac bundle-branch disorders like progressive familial heart block type I (PFHBI, Kruse et al. Journal of Clinical Investigation (2009) 119:2737-2744) and isolated cardiac conduction disease (ICCD, Liu et al., Circulation Cardiovascalur Genetics, in press) are associated in four families with a dominantly inherited mutation in the TRPM4 gene. The TRPM4 gene encodes a non-selective cation channel belonging to the transient receptor potential melastatin family of ion channels. The PFHBI and ICCD mutations do not affect TRPM4 channel properties in in vitro expression systems. Ca2+-dependence, sensitivity to phosphatidyl inositol 3,5-bisphosphate, inhibition by ATP, single channel conductance and channel open probability remained unaffected by the four mutations. However, the mutations markedly affected the amplitude of TRPM4 current (pA/pF). Using biochemical and immunocytochemical methods we show that this effect is due to an increase in the number of TRPM4 channel at the plasma membrane. Importantly, the mutational effects on TRPM4 current increase are dominant, suggesting that PFHBI and ICCD are dominantly inherited gain-of-function disorders. Cellular expression studies showed that the TRPM4 channel needs to be post translationally SUMOylated for efficient residence in the plasma membrane. Accordingly, deSUMOylation of TRPM4 removes the TRPM4 channel from the plasma membrane. By contrast, the mutant TRPM4 channels are insensitive to deSUMOylation and, thus, resilient to endocytosis. TRPM4 endocytosis involves a dynein and caveolin associated pathway, which makes TRPM4 channel density sensitive to drugs like latrunculin-B and methyl-β cyclodextrin. Apparently, TRPM4 channel activity is very sensitive to changes in the lipid composition of the plasma membrane as well as to structural changes of the underlying subcellular cortex. Taken together our data suggest that the cardiac conduction diseases PFHBI and ICCD are caused by an increased cardiac TRPM4 channel activity, most likely in the Purkinje fiber system, where the TRPM4 channel is mostly expressed. Possibly, the increased TRPM4 activity slows or even blunts cardiac conduction because of its effects on membrane depolarization and Ca2+ influx.
- © 2010 by American Heart Association, Inc.