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.
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).
D001464:Barium / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism*; D015764:Bepridil; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels; D004110:Diltiazem / Q000378:metabolism*; D005711:Gallopamil / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D011759:Pyrrolidines / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013324:Strontium / Q000378:metabolism; D014700:Verapamil / Q000031:analogs & derivatives* / Q000378:metabolism
D001552:Benzazepines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D001464:Barium; D005711:Gallopamil; D015764:Bepridil; C043184:4-desmethoxyverapamil; D014700:Verapamil; D004110:Diltiazem; D008274:Magnesium; D002118:Calcium; D013324:Strontium