Disappearance in high-K+ medium of receptor-mediated inhibition of adenylate cyclase in guinea-pig cortical slices.
The muscarinic acetylcholine receptor-mediated inhibition of adenylate cyclase was studied in slices of guinea-pig cerebral cortex under normal and depolarizing conditions. Carbachol (1 mM) inhibited basal and isoproterenol (50 microM)-stimulated cyclic AMP (cAMP) accumulation by 20% and 25%, respectively, in normal Krebs-Ringer bicarbonate buffer solution (KRB). High-K+ medium (42 mM K+) increased cAMP accumulation to 330% of the basal level and abolished the inhibitory effect of carbachol. It also abolished the effect of morphine, an agonist of opioid receptors. Low-Ca2+ KRB or the presence of the Ca2+ channel blocker nifedipine, counteracted the effect of high K+ and restored the inhibitory effect of carbachol on the cAMP level. Pretreatment of slices with W-7 or trifluoperazine, two calmodulin antagonists, had the same effect as low Ca2+ or nifedipine on high-K(+)-stimulated cAMP accumulation and caused reappearance of the inhibitory effects of carbachol and morphine. On the contrary, H-7, an inhibitor of protein kinase C, and neomycin, an inhibitor of phospholipase C, had no significant effect on high-K(+)-induced phenomena and did not restore the effect of carbachol. These data suggest that the Ca2(+)-calmodulin system activated by membrane depolarization regulates the cAMP level directly and also by affecting the receptor-mediated process in nerve cells.
Zhou
X M
XM
Department of Pharmacology I, Osaka University School of Medicine, Japan.
Uchida
S
S
Yoshida
H
H
D000110:Acetylcholinesterase / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D019832:N-Methylscopolamine; D011188:Potassium / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000067956:Adenylyl Cyclase Inhibitors; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D002217:Carbachol; D000242:Cyclic AMP; D000110:Acetylcholinesterase; D011188:Potassium; D002118:Calcium; D019832:N-Methylscopolamine