Distinct regulation of cardiac I(f) current via thyroid receptors alpha1 and beta1.
Thyroid hormone (TH) markedly modulates cardiovascular function and heart rate. The pacemaker current I(f) and encoding hyperpolarization-activated cation (HCN) genes have been identified as TH targets. To analyze the specific contribution and functional significance of thyroid receptor isoforms responsible for HCN gene transactivation, we generated transgenic neonatal rat cardiomyocytes with adenovirus-mediated overexpression of the thyroid receptors alpha1 (TR alpha 1) and beta1 (TR beta 1), and analyzed native I(f) current and expression levels of the underlying molecular components HCN2 and HCN4. Initial results revealed that spontaneous beating activity was higher in TR alpha 1- and lower in TR beta 1-expressing cardiomyocytes. This was associated with accelerated depolarization velocity and abbreviated action potential duration in cells overexpressing TR alpha 1, while TR beta 1 suppressed phase 4 depolarization and prolonged action potentials. Consistently, TR alpha 1-infected myocytes exhibited larger I(f) current densities along with increased HCN2 and HCN4 mRNA and protein levels. In contrast, HCN2 gene expression was not significantly affected by TR beta 1. TR beta 1 exclusively suppressed HCN4 transcription. T3 application led to significant effects only in controls and TR alpha 1-infected cardiomyocytes; whereas, no ligand-dependent actions were observed in TR beta 1-expressing neonatal cardiomyocytes. Our results demonstrate that TR alpha 1 and TR beta 1 divergently regulate cardiac pacing activity. TH-induced positive chronotropic effects are likely to be mediated by TR alpha 1 through enhanced expression of I(f) pacemaker current and its underlying genes.
Gassanov
Natig
N
Department of Internal Medicine III, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
Er
Fikret
F
Endres-Becker
Jeannette
J
Wolny
Martin
M
Schramm
Christoph
C
Hoppe
Uta C
UC
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000096:biosynthesis / Q000235:genetics*; D055724:Electrophysiological Phenomena; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics*; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D037021:Thyroid Hormone Receptors alpha / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*
D054815:Cyclic Nucleotide-Gated Cation Channels; C578710:HCN2 protein, human; C119587:HCN4 protein, human; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta