Activation of protein kinase C (PKC) by phorbol esters is known to sup
press M-current. 4-beta-Phorbol 12,13-dibutyrate (PDBu) irreversibly s
uppressed M-current in a concentration-dependent manner (K-i 38 nM). I
nhibitors of PKC, the pseudo-substrate peptide PKCI (19-31), staurospo
rine and 1-(5-isoquinolinylsulfonyl)2-methylpiperazine (H7) antagonize
d PDBu-mediated suppression of M-current. Suppression of M-current by
muscarine and luteinizing hormone-releasing hormone (LHRH) was unaffec
ted by PKCI (19-31) and H7, but was antagonized by staurosporine. The
balance of data suggests that suppression of M-current by agonists is
probably not mediated by activation of PKC. Addition and subsequent re
moval of PDBu to M-current suppressed by muscarine prevented the actio
n of PDBu, while closing M-channels by voltage or blocking by barium d
id not. This suggests that M-channel closure by muscarine protects tho
se channels from the effects of PDBu. Partial suppression of M-current
by low concentrations of muscarine antagonized the response to PDBu,
with the magnitude of suppression equivalent to that seen with PDBu al
one. It is suggested that two interconvertable populations of M-channe
ls exist, one that is sensitive to both agonist and PDBu and another t
hat can only be suppressed by agonist.