Article ; Online: Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity.
Proceedings of the National Academy of Sciences of the United States of America
2013 Volume 110, Issue 32, Page(s) E3037–46
Abstract: ... we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase ... for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic ... of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required ...
| 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. |
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| MeSH term(s) | Animals ; Calcium/metabolism ; Cells, Cultured ; Cyclic Nucleotide-Gated Cation Channels/genetics ; Cyclic Nucleotide-Gated Cation Channels/metabolism ; Gene Expression ; Gene Knockdown Techniques ; Heart/embryology ; Heart/physiology ; Heart Rate/genetics ; Heart Rate/physiology ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Membrane Potentials/genetics ; Membrane Potentials/physiology ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Myocardium/cytology ; Myocardium/metabolism ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/physiology ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sinoatrial Node/cytology ; Sinoatrial Node/embryology ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/physiology ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism |
| Chemical Substances | Cyclic Nucleotide-Gated Cation Channels ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; TRPM Cation Channels ; Zebrafish Proteins ; Trpm7 protein, mouse (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Trpm7 protein, zebrafish (EC 2.7.11.1) ; Calcium (SY7Q814VUP) |
| Language | English |
| Publishing date | 2013-07-22 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 209104-5 |
| ISSN | 1091-6490 ; 0027-8424 |
| ISSN (online) | 1091-6490 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.1311865110 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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