The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels encode neuronal and cardiac pacemaker currents. The composition of pacemaker channel complexes in different tissues is poorly understood, and the presence of additional HCN modulating subunits was speculated. Here we show that vesicle-associatedmembrane protein-associated protein B (VAPB), previously associatedwith a familial form of amyotrophic lateral sclerosis 8, is an essential HCN1 and HCN2 modulator. VAPB significantly increases HCN2 currents and surface expression and has amajor influenceon the dendritic neuronal distribution of HCN2. Severe cardiacbradycardias inVAPB-deficient zebrafish and VAPB-/- mice highlight that VAPB physiologically serves to increase cardiac pacemaker currents. An altered T-wave morphology observed in the ECGs of VAPB-/- mice supports the recently proposed role of HCN channels for ventricular repolarization.The critical function ofVAPBin native pacemaker channel complexes will be relevant forourunderstanding of cardiac arrhythmias andepilepsies,andprovides anunexpectedlinkbetweenthese diseases and amyotrophic lateral sclerosis.