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Characterization of the Ca2+ coordination site regulating binding of Ca2+ channel inhibitors d-cis-diltiazem, (+/-)bepridil and (-)desmethoxyverapamil to their receptor site in skeletal muscle transverse tubule membranes
Authors:J P Galizzi  M Fosset  M Lazdunski
Institution:Chemistry Department, S.U.N.Y. at Stony Brook, Stony Brook, N.Y. 11794, USA
Abstract:Ca2+ inhibits (-)3H]desmethoxyverapamil, d-cis-3H]diltiazem and (+/-)3H]bepridil binding to skeletal muscle transverse-tubule membranes with a half-maximum inhibition constant, K0.5 = 5 +/- 1 microM. This value is close to that of the high affinity Ca2+ binding site which controls the ionic selectivity of the Ca2+ channel found in electrophysiological experiments suggesting that the Ca2+ coordination site which regulates the ionic selectivity is also the one which alters binding of the Ca2+ channel inhibitors investigated here. Ca2+ and (-)D888 bind to distinct sites. Occupation of the Ca2+ coordination site decreases the affinity of (-)D888 for its receptor by a factor of 5. Other divalent cations have the same type of inhibition behavior with the rank order of potency Ca2+ (K0.5 = 5 microM) greater than Sr2+ (K0.5 = 25 microM) greater than Ba2+ (K0.5 = 50 microM) greater than Mg2+ (K0.5 = 170 microM).
Keywords:Monobromobimane  3  6  7 trimethyl-4 bromomethyl-1  5-diazabicyclo [3  3  0]octa-3  6-diene-2  8-dione
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