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-associated membrane protein–associated protein B (VAPB), previously associated with 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 a major influence on the dendritic neuronal distribution of HCN2. Severe cardiac bradycardias in VAPB-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 of VAPB in native pacemaker channel complexes will be relevant for our understanding of cardiac arrhythmias and epilepsies, and provides an unexpected link between these diseases and amyotrophic lateral sclerosis.—Silbernagel, N., Walecki, M., Schäfer, M.-K. H., Kessler, M., Zobeiri, M., Rinné, S., Kiper, A. K., Komadowski, M. A., Vowinkel, K. S., Wemhöner, K., Fortmüller, L., Schewe, M., Dolga, A. M., Scekic-Zahirovic, J., Matschke, L. A., Culmsee, C., Baukrowitz, T., Monassier, L., Ullrich, N. D., Dupuis, L., Just, S., Budde, T., Fabritz, L., Decher, N. The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function.
Highlights
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a major role in generating neuronal and cardiac automaticity (1)
Using a split-ubiquitin yeast 2-hybrid (Y2H) (30) screen with the full-length HCN2 channel as a bait to search for plasma membrane– bound channel modulators, vesicle-associated membrane protein–associated protein B (VAPB) was identified from a human adult brain cDNA library as a potential HCN2 interacting partner
VAP proteins are anchored with a C-terminal TM domain in the cell membrane, contain a conserved N-terminal major sperm region (MSP) and an amphipathic coiled-coil domain (CC), which is a common motif in t-synaptosome-associated protein receptor (SNARE) (31) (Fig. 1B)
Summary
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a major role in generating neuronal and cardiac automaticity (1). ABBREVIATIONS: ALS, amyotrophic lateral sclerosis; CC, coiled-coil; CNBD, cyclic nucleotide–binding domain; DIG, digoxigenin; ECG, electrocardiogram; GFP, green fluorescent protein; GST, glutathione S-transferase; HA, hemagglutinin; HCN, hyperpolarization-activated cyclic nucleotide-gated; hpf, hours postfertilization; iPSC-CM, induced pluripotent stem cell–derived cardiomyocyte; ISH, in situ hybridization; I–V, current–voltage; MO, morpholino-modified antisense oligonucleotide; MSP, major sperm region; Pir, piriform cortex; shRNA, short hairpin RNA; SSC, saline-sodium citrate; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TEVC, two-electrode voltage-clamp; TM, transmembrane; VAMP, vesicleassociated membrane protein; VAPB, VAMP-associated protein B; Y2H, yeast 2-hybrid Previous studies of Kv2.1 and VAMP (19), TASK1 and syntaxin 8 (20), or GLUT4 and VAPA (15) indicated that components of the v-SNARE or target (t)-SNARE complex (t-SNARE) might have functions in addition to regulating exocytosis, as they modulate channels or transporters that are integral to the surface/cell membrane
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