The antidepressant imipramine inhibits M current by activating a phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent pathway in rat sympathetic neurones.
Little is known about the intracellular actions of imipramine (IMI) in the regulation of ion channels. We tested the action of IMI on the intracellular cascade that regulates M current (I(M)) in superior cervical ganglion neurones (SCGs). Dialysis of the cells with GDPbetaS, a G protein signaling blocker, did not disrupt the inhibition of I(M). When we incubated the cells with the phospholipase C (PLC) inhibitor U73122, it prevented the I(M) inhibition by IMI. Also, when we dialyzed the cells with an intracellular Ca2+ chelator, it did not disrupt I(M) inhibition by IMI, as occurs in the M1 cascade. When we incubated the cells with the generic kinase inhibitor wortmannin, it prevented the recovery of I(M) from the inhibition by IMI. Also, when we applied phosphatidylinositol 4,5-bisphosphate (PIP2) intracellularly, it diminished the inhibition of I(M) by IMI. Our findings suggest that PLC is the target for IMI, that recovery of I(M) needs lipid phosphorylation for PIP2 resynthesis, and that IMI inhibits I(M) by activating a PLC-dependent pathway, likely by decreasing the concentration of PIP2.
Quintero
Jania L
JL
Department of Physiology, Faculty of Medicine, UNAM, Apdo. Post. 70250, CP 04510 México, DF, México.
Arenas
Maria Isabel
MI
García
David E
DE
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002478:Cells, Cultured; D007099:Imipramine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017783:Superior Cervical Ganglion / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D019269:Phosphatidylinositol 4,5-Diphosphate; D024642:Potassium Channels, Voltage-Gated; D010738:Type C Phospholipases; D007099:Imipramine