Glucocorticoid induction of Kv1.5 K+ channel gene expression in ventricle of rat heart.
Multiple voltage-gated K+ channels contribute to the repolarization phases of the cardiac action potential and are targets of several antiarrhythmic drugs. The Kv1.5 K+ channel gene is expressed in the heart, and heterologous expression of this gene generates a slowly inactivating K+ current. Previously, we found that glucocorticoids specifically upregulate pituitary Kv1.5 gene expression. To test whether these steroids might also induce Kv1.5 gene expression in the heart, cardiac channel mRNA and protein were measured by RNase protection assay and by immunoblotting with antibody specific for the extracellular domain of Kv1.5 polypeptide. Kv1.5 mRNA and immunoreactive protein appeared to be more abundant in rat ventricle than atrium. Reduction of endogenous glucocorticoids by adrenalectomy decreased ventricular Kv1.5 mRNA approximately 8-fold, which was estimated by using cyclophilin mRNA as an internal control. Kv1.5 immunoreactive protein also decreased approximately 6-fold. Injection of dexamethasone into adrenalectomized rats acted within a day to increase ventricular Kv1.5 mRNA and immunoreactive protein approximately 50-fold and approximately 20-fold, respectively. In contrast, atrial Kv1.5 mRNA expression was unaffected by either adrenalectomy or injection of the glucocorticoid agonist. Furthermore, dexamethasone-induced upregulation was specific for Kv1.5, since whole-heart Kv1.4 and Kv2.1 mRNA levels, as well as ventricular Kv2.1 mRNA expression, were unchanged. Thus, dexamethasone specifically upregulates Kv1.5 K+ channel gene expression in rat ventricle but not atrium. Glucocorticoids may affect excitability of ventricular myocytes and the efficacy of clinically useful drugs by changing the expression of the Kv1.5 K+ channel.
Department of Pharmacology, University of Pittsburgh, PA 15261.
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Takimoto
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Levitan
D000315:Adrenalectomy; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology*; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015854:Up-Regulation
D005938:Glucocorticoids; D015221:Potassium Channels; D012333:RNA, Messenger; D003907:Dexamethasone