1006 Glucocorticoid Induction of Kvl . 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 Kvl.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 Kvl.5 gene expression. To test whether these steroids might also induce Kvl.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 Kvl.5 polypeptide. Kvl.5 mRNA and immunoreactive protein appeared to be more abundant in rat ventricle than atrium. Reduction of endogenous glucocorticoids by adrenalectomy decreased ventricular Kvl.5 mRNA :'8-fold, which was estimated by using cyclophilin mRNA as an internal control. Kvl.5 immunoreacM ultiple voltage-gated K' channels participate in the various repolarization phases of the cardiac action potential. Molecular biological studies have shown that at least seven distinct voltage-gated K' channel genes are expressed in rat cardiac tissues.1-3 These include four Shaker-related or Kvl subfamily genes: Kvl.1, Kv1.2, Kv1.4, and Kv1.5.12 Studies with heterologous expression systems have revealed that Kvl.1, Kv1.2, and Kvl.5 genes encode slowly inactivating channels,2,45 whereas the Kvl.4 gene encodes a rapidly inactivating channel.467 Furthermore, these channel gene products can form heteromeric K' channels that exhibit current kinetics and pharmacological properties distinct from the original homomeric channels.8-13 For example, coexpression of Kvl.4 and Kvl.5 in Xenopus oocytes generates heteromeric K' channels with intermediate inactivation kinetics.14,15 Hence, the diversity of voltage-gated K' currents in cardiac tissues may be due to expression of multiple gene products that assemble into a variety of homomeric and heteromeric channels. The existence of multiple K' channel genes may also allow for differential control of channel expression. It is known that the expression of K' channel mRNAs varies between regions of rat heart: significant amounts of transcripts for Kvl.1, Kv1.2, Kv1.4, Kvl.5, and Kv2.1 are detected in the rat atrium, whereas only the last two channel mRNAs are abundant in the ventricle.' MoreReceived May 17, 1994; accepted September 7, 1994. From the Department of Pharmacology, University of Pittsburgh (Pa). Correspondence to Dr Edwin S. Levitan, Department of Pharmacology, University of Pittsburgh, 13th Floor, Biomedical Science Tower, Pittsburgh, PA 15261. C) 1994 American Heart Association, Inc. tive protein also decreased =6-fold. Injection of dexamethasone into adrenalectomized rats acted within a day to increase ventricular Kvl.5 mRNA and immunoreactive protein :50fold and ~z20-fold, respectively. In contrast, atrial Kvl.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 Kvl.4 and Kv2.1 mRNA levels, as well as ventricular Kv2.1 mRNA expression, were unchanged. Thus, dexamethasone specifically upregulates Kvl.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 Kvl.5 K' channel. (Circ Res. 1994;75:1006-1013.)