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 phenylephrine (PE) on acetylcholine-activated K(+) currents (I(KACh)). I(KACh) was recorded in mouse atrial myocytes using the patch clamp technique. I(KACh) was activated by 10 microm ACh and the current decreased by 44.27 +/- 2.38% (n = 12) during 4 min due to ACh-induced desensitization. When PE was applied with ACh, 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 desensitization of I(KACh) was not affected by protein kinase C inhibitor, calphostin C, but abolished by phospholipase C (PLC) inhibitor, neomycin. When phophatidylinositol 4,5-bisphosphate (PIP(2)) replenishment was blocked by wortmannin (an inhibitor of phophatidylinositol 3-kinase and phophatidylinositol 4-kinase), desensitization of I(KACh) in the presence of PE was further increased (97.25 +/- 7.63%, n = 6). Furthermore, the recovery from PE-induced desensitization was inhibited, and the amplitude of I(KACh) at the second exposure after washout was reduced to 19.65 +/- 2.61% (n = 6) of the preceding level. These data suggest that the K(ACh) channel is modulated by PE through PLC stimulation and depletion of PIP(2).
Cho
H
H
National Research Laboratory for Cellular Signalling, Seoul National University College of Medicine, 28 Yonkeun-Dong, Chongno-Ku, Seoul 110-799, Korea.
Nam
G B
GB
Lee
S H
SH
Earm
Y E
YE
Ho
W K
WK
D000109:Acetylcholine / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077191:Wortmannin
D000316:Adrenergic alpha-Agonists; D000730:Androstadienes; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009281:Naphthalenes; D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D010656:Phenylephrine; D011493:Protein Kinase C; D010738:Type C Phospholipases; D009355:Neomycin; C058819:calphostin C; D000109:Acetylcholine; D000077191:Wortmannin