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CARDIOVASCULAR

Estrogen Receptor Mediates Acute Potassium Channel Stimulation in Human Coronary Artery Smooth Muscle Cells

Department of Pharmacology and Toxicology (G.H., R.E.W., H.M., S.Z.) and Institute of Molecular Medicine and Genetics (S.L.), Medical College of Georgia, Augusta, Georgia; Division of Molecular Medicine, Harbor UCLA Medical Center, Los Angeles, California (L.L.); Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee (X.Y.); and Department of Biochemistry, Dalian Medical University, Dalian, China (X.C.)

The pleiotropic effects of estrogen are mediated via stimulation of two estrogen receptor (ER) subtypes, ER and ER. Although a number of studies have identified expression of one or both subtypes in estrogen target tissues, fewer studies have correlated ER expression with a functional role of these proteins in regulating cellular excitability. In the present study, we have combined cellular fluorescence, immunocytochemistry, and molecular expression techniques with single-channel patch-clamp studies to determine which ER mediates estrogen-stimulated potassium channel activity in human coronary artery smooth muscle cells (HCASMC). We had demonstrated previously that estrogen stimulates activity of the large-conductance, calcium- and voltage-activated potassium (BK_Ca) channel in HCASMC via a nongenomic mechanism. We now demonstrate expression of both ER and ER subtypes in HCASMC. Functionally, however, expression of ER antisense plasmid abolished the acute effect of estrogen on these channels, whereas estrogen retained its ability to stimulate BK_Ca channels in cells transfected with only green fluorescence protein. In contrast, overexpression of ER enhanced the stimulatory action of estrogen in HCASMC. Transfection with ER antisense/sense plasmid did not alter ER expression. These findings indicate that the ER isoform mediates estrogen-induced stimulation of BK_Ca channels in HCASMC and thereby provide evidence for a receptor-dependent signaling mechanism that can mediate estrogen-induced inhibition of cellular excitability.

Address correspondence to: Dr. Guichun Han, Dept. Pharmacology and Toxicology, 1120 15th Street, Augusta, GA. E-mail: ghan{at}mail.mcg.edu

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