Phosphatidylinositol 4,5-bisphosphate is acting as a signal molecule in alpha(1)-adrenergic pathway via the modulation of acetylcholine-activated K+ channels in mouse atrial myocytes

We have investigated the effect of alpha (1)-adrenergic agonist phenylephri ne (PE) on acetylcholine-activated K+ currents (I-KACh). I-KACh was recorde d in mouse atrial myocytes using the patch clamp technique. I-KACh was acti vated by 10 muM ACh and the current decreased by 44.27 +/- 2.38% (n = 12) d uring 4 min due to ACh-induced desensitization. When PE was applied with AC h, the extent of desensitization was markedly increased to 69.34 +/- 2.22% (n = 9), indicating the presence of PE-induced desensitization, I-KACh was fully recovered from desensitization after a 6-min washout. PE-induced dese nsitization of I-KACh was not affected by protein kinase C inhibitor, calph ostin C, but abolished by phospholipase C (PLC) inhibitor, neomycin, When p hophatidylinositol 4,5-bisphosphate (PIP2) replenishment was blocked by wor tmannin (an inhibitor of phophatidylinositol 3-kinase and phophatidylinosit ol 4-kinase), desensitization of I,,, in the presence of PE was further inc reased (97.25 +/- 7.63%, n = 6), Furthermore, the recovery from PE-induced desensitization was inhibited, and the amplitude of I,, at the second expos ure after washout was reduced to 19.65 +/- 2.61% (n = 6) of the preceding l evel. These data suggest that the K-ACh, channel is modulated by PE through PLC stimulation and depletion of PIP2.