title: Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity.
abstract: Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca(2+) transient firing rates and is associated with robust down-regulation of Hcn4, Cav3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO(αMHC-Cre)), and tamoxifen-inducible SAN restricted Trpm7 deletion (KO(HCN4-CreERT2)) disrupts cardiac automaticity in vivo. Telemetered and sedated KO(αMHC-Cre) and KO(HCN4-CreERT2) mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO(αMHC-Cre) mice exhibit diminished Ca(2+) transient firing rates with a blunted diastolic increase in Ca(2+). Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, I(f), are diminished in SAN from both KO(αMHC-Cre) and KO(HCN4-CreERT2) mice. Moreover, heart rates of KO(αMHC-Cre) mice are less sensitive to the selective I(f) blocker ivabradine, and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Sah
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.forename: Marjolein
authors.initials: M
authors.lastname: Van den Boogert
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosen
authors.forename: John
authors.initials: J
authors.lastname: Mably
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012849:Sinoatrial Node / Q000166:cytology / Q000196:embryology; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D050053:TRPM Cation Channels; D029961:Zebrafish Proteins; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C501875:Trpm7 protein, zebrafish; D002118:Calcium
keywords: arrhythmia; confocal; electrocardiogram; electrophysiology