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BAY 41‐2272, a potent activator of soluble guanylyl cyclase, stimulates calcium elevation and calcium‐activated potassium current in pituitary GH 3 cells
Author(s) -
Liu YenChin,
Wu ShengNan
Publication year - 2005
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2005.04315.x
Subject(s) - soluble guanylyl cyclase , activator (genetics) , calcium , endocrinology , medicine , chemistry , guanylate cyclase , bay , potassium , biology , receptor , geology , oceanography , organic chemistry
Summary 1. The effects of BAY 41‐2272, a nitric oxide‐independent activator of soluble guanylyl cyclase, on Ca 2+ signalling and ion currents were investigated in pituitary GH 3 cells. 2. Intracellular Ca 2+ concentrations ([Ca 2+ ] i ) in these cells were increased by BAY 41‐2272. Removing extracellular Ca 2+ abolished the BAY 41‐2272‐induced increase in [Ca 2+ ] i . After [Ca 2+ ] i was elevated by BAY 41‐2272 (300 nmol/L), subsequent application of 1‐benzyl‐3‐(5′‐hydroxymethyl‐2′‐furyl) indazole (YC‐1; 1 μmol/L) did not increase [Ca 2+ ] i further. 3. In whole‐cell recordings, BAY 41‐2272 reversibly stimulated Ca 2+ ‐activated K + current (I K(Ca) ) with an EC 50 of 225 ± 8 nmol/L. At 3 μmol/L, BAY 41‐2272 slightly and significantly decreased L‐type Ca 2+ current. 4. In the cell‐attached configuration, BAY 41‐2272 (300 nmol/L) enhanced the activity of large‐conductance Ca 2+ ‐activated K + (BK Ca ) channels. After BK Ca channel activity was stimulated by spermine NONOate (30 μmol/L) or YC‐1 (10 μmol/L) in cell‐attached patches, subsequent application of BAY 41‐2272 (300 nmol/L) further increased the channel open probability. 5. In the inside‐out configuration, BAY 41‐2272 applied to the intracellular surface of excised patches enhanced BK Ca channel activity. Unlike 1 µmol/L paxilline, 1 H ‐[1,2,4]oxadiazolol‐[4,3a] quinoxalin‐1‐one (ODQ; 10 μmol/L) or heme (10 μmol/L) had no effect on BAY 41‐2272‐stimulated channel activity. BAY 41‐2272 caused no shift in the activation curve of BK Ca channels; however, it did increase the Ca 2+ sensitivity of these channels. 6. At 300 nmol/L, BAY 41‐2272 reduced the firing rate of spontaneous action potentials stimulated by thyrotropin‐releasing hormone (10 μmol/L). The BK Ca channel activity was also enhanced by 300 nmol/L BAY 41‐2272 in neuroblastoma IMR‐32 cells. 7. Therefore, the BAY 41‐2272‐induced increase in [Ca 2+ ] i is primarily explained by an increase in Ca 2+ influx. The BAY 41‐2272‐mediated simulation of I K(Ca) may result from direct activation of BK Ca channels and indirectly as a result of elevated [Ca 2+ ] i .