Activation of BK(Ca) channel via endothelin ET(A) receptors in porcine coronary artery smooth muscle cells.
It has been demonstrated previously that endothelin-1 stimulates the Ca2+-activated K+ (BK(Ca)) channel activity in porcine coronary artery smooth muscle cells. The purpose of the present study was to delineate the endothelin receptor subtype involved in this action. In receptor binding studies, [125I]endothelin-1 was shown to bind to the homogenate of porcine primary coronary artery smooth muscle cells in a single class of binding sites with K(D) and Bmax values of 73 pM and 99 fmol/mg protein, respectively. Furthermore, endothelin-1 and endothelin-3 displaced the binding of [125I]endothelin-1 to these cells with respective IC50 values of 70 and 17000 pM, a 240-fold difference in potency. The effects of endothelin-3 on the activity of the BK(Ca) channel in porcine coronary artery smooth muscle cells were examined using the cell-attached patch-clamp technique. Similar to endothelin-1, endothelin-3 also exhibited a bell-shaped concentration-response curve. A maximal increase of 95% in channel open-state probability (Po) was induced by 100 nM endothelin-3 as compared with the 320% increase in Po by 1 nM endothelin-1. Thus, endothelin-1 was about 100-fold more potent and 3.4-fold more efficacious than endothelin-3 in this action. Both the receptor binding and the electrophysiological results suggest that the effects of endothelins on the BK(Ca) channel are mediated through the endothelin ET(A) receptor subtype.
Hu
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Research Department, Novartis Pharmaceuticals, Summit, NJ 07901, USA.
Kim
H S
HS
Savage
P
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Jeng
A Y
AY
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
D019332:Endothelin-1; D019334:Endothelin-3; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D017466:Receptors, Endothelin; D002118:Calcium