XB-ART-56127
FASEB J
January 1, 2018;
32
(11):
6159-6173.
The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function.
Silbernagel N
,
Walecki M
,
Schäfer MK
,
Kessler M
,
Zobeiri M
,
Rinné S
,
Kiper AK
,
Komadowski MA
,
Vowinkel KS
,
Wemhöner K
,
Fortmüller L
,
Schewe M
,
Dolga AM
,
Scekic-Zahirovic J
,
Matschke LA
,
Culmsee C
,
Baukrowitz T
,
Monassier L
,
Ullrich ND
,
Dupuis L
,
Just S
,
Budde T
,
Fabritz L
,
Decher N
.
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.
PubMed ID: 29879376
PMC ID: PMC6629115
Article link: FASEB J
Grant support: [+]
FS/13/43/30324 British Heart Foundation
Species referenced: Xenopus laevis
Genes referenced: hcn1 hcn2 hcn4 map2 mst1 ncl nectin3
GO keywords: cyclic nucleotide binding
Disease Ontology terms: epilepsy
OMIMs: AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8
Article Images: [+] show captions
References [+] :
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Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord.
2010, Pubmed
Anagnostou,
Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord.
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Pubmed
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Biel, Cardiac HCN channels: structure, function, and modulation. 2002, Pubmed
Chen, Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel. 2000, Pubmed , Xenbase
Chen, HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents. 2006, Pubmed
Claycomb, HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. 1998, Pubmed
Decher, Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia. 2017, Pubmed
DiFrancesco, Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. 1991, Pubmed
DiFrancesco, Dysfunctional HCN ion channels in neurological diseases. 2015, Pubmed
DiFrancesco, Pacemaker mechanisms in cardiac tissue. 1993, Pubmed
Doherty, Mechanisms of endocytosis. 2009, Pubmed
Dolga, KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. 2011, Pubmed
Estévez, Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. 2002, Pubmed , Xenbase
Fenske, HCN3 contributes to the ventricular action potential waveform in the murine heart. 2011, Pubmed
Fenske, Sick sinus syndrome in HCN1-deficient mice. 2014, Pubmed
Fenske, The role of HCN channels in ventricular repolarization. 2013, Pubmed
Finsterer, Sudden cardiac death in neuromuscular disorders. 2016, Pubmed
Foster, A functional role for VAP-33 in insulin-stimulated GLUT4 traffic. 2001, Pubmed
Friedrich, Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder. 2015, Pubmed , Xenbase
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Hofmann, Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. 2012, Pubmed
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Kabashi, Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. 2013, Pubmed
Kanyshkova, Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations. 2009, Pubmed
Keßler, Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish. 2015, Pubmed
Langenbacher, Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish. 2006, Pubmed
Leroy, Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. 2016, Pubmed
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Lvov, VAMP2 interacts directly with the N terminus of Kv2.1 to enhance channel inactivation. 2009, Pubmed , Xenbase
Marques, Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. 2007, Pubmed
Marques, Neurophysiological findings of the late-onset, dominant, proximal spinal muscular atrophies with dysautonomia because of the VAPB PRO56SER mutation. 2008, Pubmed
Meder, Reconstitution of defective protein trafficking rescues Long-QT syndrome in zebrafish. 2011, Pubmed
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Nishimura, A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. 2005, Pubmed
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Pape, Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. 1989, Pubmed
Pape, Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. 1996, Pubmed
Renigunta, Cooperative endocytosis of the endosomal SNARE protein syntaxin-8 and the potassium channel TASK-1. 2015, Pubmed , Xenbase
Roselli, From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases. 2015, Pubmed
Santoro, Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. 2005, Pubmed , Xenbase
Santoro, TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. 2009, Pubmed
Santoro, Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. 1998, Pubmed , Xenbase
Saponaro, Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function. 2015, Pubmed
Sartiani, Functional expression of the hyperpolarization-activated, non-selective cation current I(f) in immortalized HL-1 cardiomyocytes. 2003, Pubmed
Saxena, Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. 2013, Pubmed
Shemisa, Autonomic etiology of heart block in amyotrophic lateral sclerosis: a case report. 2015, Pubmed
Shimizu, Circulatory collapse and sudden death in respirator-dependent amyotrophic lateral sclerosis. 1994, Pubmed
Skehel, Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. 2000, Pubmed
Skehel, A VAMP-binding protein from Aplysia required for neurotransmitter release. 1995, Pubmed
Soussan, ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles. 1999, Pubmed
Teuling, Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. 2007, Pubmed
Weimbs, A conserved domain is present in different families of vesicular fusion proteins: a new superfamily. 1997, Pubmed
Weir, Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP. 1998, Pubmed
Williams, Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. 2000, Pubmed
Zolles, Pacemaking by HCN channels requires interaction with phosphoinositides. 2007, Pubmed , Xenbase
Zolles, Association with the auxiliary subunit PEX5R/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation. 2009, Pubmed , Xenbase
Asai, Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS. 2007, Pubmed
Beaumont, Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. 2000, Pubmed
Biel, Cardiac HCN channels: structure, function, and modulation. 2002, Pubmed
Chen, Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel. 2000, Pubmed , Xenbase
Chen, HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents. 2006, Pubmed
Claycomb, HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. 1998, Pubmed
Decher, Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia. 2017, Pubmed
DiFrancesco, Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. 1991, Pubmed
DiFrancesco, Dysfunctional HCN ion channels in neurological diseases. 2015, Pubmed
DiFrancesco, Pacemaker mechanisms in cardiac tissue. 1993, Pubmed
Doherty, Mechanisms of endocytosis. 2009, Pubmed
Dolga, KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. 2011, Pubmed
Estévez, Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. 2002, Pubmed , Xenbase
Fenske, HCN3 contributes to the ventricular action potential waveform in the murine heart. 2011, Pubmed
Fenske, Sick sinus syndrome in HCN1-deficient mice. 2014, Pubmed
Fenske, The role of HCN channels in ventricular repolarization. 2013, Pubmed
Finsterer, Sudden cardiac death in neuromuscular disorders. 2016, Pubmed
Foster, A functional role for VAP-33 in insulin-stimulated GLUT4 traffic. 2001, Pubmed
Friedrich, Gain-of-function mutation in TASK-4 channels and severe cardiac conduction disorder. 2015, Pubmed , Xenbase
Gkogkas, VAPB interacts with and modulates the activity of ATF6. 2008, Pubmed
Han, Trafficking and gating of hyperpolarization-activated cyclic nucleotide-gated channels are regulated by interaction with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) and cyclic AMP at distinct sites. 2011, Pubmed
Hofmann, Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. 2012, Pubmed
Hu, Binding of the auxiliary subunit TRIP8b to HCN channels shifts the mode of action of cAMP. 2014, Pubmed , Xenbase
Johnsson, Split ubiquitin as a sensor of protein interactions in vivo. 1994, Pubmed
Kabashi, Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. 2013, Pubmed
Kanyshkova, Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations. 2009, Pubmed
Keßler, Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish. 2015, Pubmed
Langenbacher, Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish. 2006, Pubmed
Leroy, Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. 2016, Pubmed
Lev, The VAP protein family: from cellular functions to motor neuron disease. 2008, Pubmed
Lewis, Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. 2009, Pubmed
Ludwig, A family of hyperpolarization-activated mammalian cation channels. 1998, Pubmed
Ludwig, Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. 2003, Pubmed
Lvov, VAMP2 interacts directly with the N terminus of Kv2.1 to enhance channel inactivation. 2009, Pubmed , Xenbase
Marques, Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. 2007, Pubmed
Marques, Neurophysiological findings of the late-onset, dominant, proximal spinal muscular atrophies with dysautonomia because of the VAPB PRO56SER mutation. 2008, Pubmed
Meder, Reconstitution of defective protein trafficking rescues Long-QT syndrome in zebrafish. 2011, Pubmed
Mitne-Neto, Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. 2012, Pubmed
Murata, An abnormal relationship between blood pressure and pulse rate in amyotrophic lateral sclerosis. 1997, Pubmed
Nishimura, A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. 2005, Pubmed
Nishimura, Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins. 1999, Pubmed
Pape, Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. 1989, Pubmed
Pape, Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. 1996, Pubmed
Renigunta, Cooperative endocytosis of the endosomal SNARE protein syntaxin-8 and the potassium channel TASK-1. 2015, Pubmed , Xenbase
Roselli, From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases. 2015, Pubmed
Santoro, Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. 2005, Pubmed , Xenbase
Santoro, TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. 2009, Pubmed
Santoro, Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. 1998, Pubmed , Xenbase
Saponaro, Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function. 2015, Pubmed
Sartiani, Functional expression of the hyperpolarization-activated, non-selective cation current I(f) in immortalized HL-1 cardiomyocytes. 2003, Pubmed
Saxena, Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. 2013, Pubmed
Shemisa, Autonomic etiology of heart block in amyotrophic lateral sclerosis: a case report. 2015, Pubmed
Shimizu, Circulatory collapse and sudden death in respirator-dependent amyotrophic lateral sclerosis. 1994, Pubmed
Skehel, Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. 2000, Pubmed
Skehel, A VAMP-binding protein from Aplysia required for neurotransmitter release. 1995, Pubmed
Soussan, ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles. 1999, Pubmed
Teuling, Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. 2007, Pubmed
Weimbs, A conserved domain is present in different families of vesicular fusion proteins: a new superfamily. 1997, Pubmed
Weir, Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP. 1998, Pubmed
Williams, Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. 2000, Pubmed
Zolles, Pacemaking by HCN channels requires interaction with phosphoinositides. 2007, Pubmed , Xenbase
Zolles, Association with the auxiliary subunit PEX5R/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation. 2009, Pubmed , Xenbase