Calcium channels in rat brain synaptosomes: identification and pharmacological characterization. High affinity blockade by organic Ca2+ channel blockers.
Rat brain synaptosomes are shown to contain functional voltage-sensitive Ca2+ channels that are inhibited by organic Ca2+ channel blockers. Depolarization of synaptosomes with high K+ stimulates uptake of 45Ca2+ which is biphasic in its time course. Replacement of external Na+ with choline eliminates the slower phase of depolarization-stimulated Ca2+ uptake, leaving only a rapid uptake process which terminates within 1 sec. This rapid, tetrodotoxin-insensitive Ca2+ uptake can be inactivated by prior depolarization of the synaptosomes. Depolarization has no effect on the rate of synatptosomal 22Na+ efflux. These results are interpreted as ruling out Na+/Ca2+ exchange as a mediator of the rapid phase of depolarization-stimulated Ca2+ uptake. A portion (30 to 50%) of the rapid phase of depolarization-stimulated Ca2+ uptake is inhibited by nitrendipine, as is depolarization-stimulated [3H]norepinephrine release from synaptosomes. In external Na+, the inhibition constant (Kapp) for nitrendipine inhibition of Ca2+ uptake is 56 nM. The potency of nitrendipine is increased in the absence of external Na+ (Kapp = 1.7 nM), such that inhibition correlates more closely with the equilibrium dissociation constant for [3H] nitrendipine binding to synaptosomes (Kd = 0.35 nM). Other organic channel blockers (nifedipine, verapamil, D600, and dilitiazem) inhibit the rapid Ca2+ uptake. The potencies of all Ca2+ channel blockers tested by us are in reasonable agreement with their potencies, observed in other laboratories, as blockers of Ca2+ channels in smooth and cardiac muscle. These data demonstrate the existence of active voltage-sensitive Ca2+ channels in synaptosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
Turner
T J
TJ
Goldin
S M
SM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives / Q000378:metabolism; D009568:Nitrendipine; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000378:metabolism*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007473:Ion Channels; D011725:Pyridines; C038806:1,4-dihydropyridine; D009568:Nitrendipine; D009543:Nifedipine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine