Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity
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 T ransient R eceptor P otential M elastatin 7 (TRPM7), a divalent-permeant channel-...
Saved in:
Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 32; pp. E3037 - E3046 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
06.08.2013
National Acad Sciences |
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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 T ransient R eceptor P otential M elastatin 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 , Ca ᵥ3.1 , and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO ᵅᴹᴴC⁻Cʳᵉ), and tamoxifen-inducible SAN restricted Trpm7 deletion (KO ᴴCᴺ⁴⁻Cʳᵉᴱᴿᵀ²) disrupts cardiac automaticity in vivo. Telemetered and sedated KO ᵅᴹᴴC⁻Cʳᵉ and KO ᴴCᴺ⁴⁻Cʳᵉᴱᴿᵀ² mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO ᵅᴹᴴC⁻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 ᵅᴹᴴC⁻Cʳᵉ and KO ᴴCᴺ⁴⁻Cʳᵉᴱᴿᵀ² mice. Moreover, heart rates of KO ᵅᴹᴴC⁻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. |
---|---|
Bibliography: | http://dx.doi.org/10.1073/pnas.1311865110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by David E. Clapham, June 25, 2013 (sent for review May 26, 2013) Author contributions: R.S. and D.E.C. designed research; R.S., P.M., M.V.d.B., and J.R. performed research; R.S. and J.M. contributed new reagents/analytic tools; R.S., P.M., and M.E.M. analyzed data; and R.S. and D.E.C. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1311865110 |