Effect of membrane depolarization by high K+ on carbachol-stimulated phosphoinositides hydrolysis in guinea pig cerebral cortical slices.
Stimulation of phosphoinositide hydrolysis by carbachol was studied in slices of guinea pig cerebral cortex under normal conditions (4.7 mM K+) and depolarization conditions with high K+ (42 mM K+). Slices were labeled with [myo-3H]-inositol, and the effects of carbachol and high K+ on the formation of inositol-bisphosphates (IP2) and inositol-trisphosphates (IP3) were determined. Carbachol (10 mM) caused only 140% stimulation of the formations of IP2 and IP3 over the control value in normal Krebs Ringer Buffer (KRB), but about 200% stimulation in high K+ medium. Dose-response curves for the effect of carbachol on the formations of IP2 and IP3 showed that high K+ medium selectively decreased the ED50 value of carbachol for IP2 formation about 3-fold. A Ca++ channel blocker, verapamil, inhibited the synergistic effect of carbachol and high K+ on IP2 formation, and a decrease in extracellular Ca++ also inhibited IP2 formation induced by high K+, but these treatments had little, if any, effect on IP3 formation. The possibility that IP2 may be directly generated by hydrolysis of phosphatidylinositol 4-monophosphate (PIP) as well as from hydrolysis of IP3 was discussed.
Zhou
X M
XM
Department of Pharmacology I, Osaka University Medical School, Japan.
Uchida
S
S
Mizushima
A
A
Yoshida
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents; D010716:Phosphatidylinositols / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D009467:Neuromuscular Depolarizing Agents; D010716:Phosphatidylinositols; D002217:Carbachol; D014700:Verapamil; D011188:Potassium; D002118:Calcium