Modulation of the inwardly rectifying K+ channel in isolated human atrial myocytes by alpha 1-adrenergic stimulation.
We have examined the alpha 1-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) in isolated human atrial myocytes using the patch clamp technique. alpha 1-Adrenergic agonist methoxamine produced action potential prolongation and a depolarization of the resting membrane potential. Under whole-cell voltage-clamp conditions, bath application of methoxamine can inhibit macroscopic IK1. The methoxamine-induced inhibition was reversible and concentration dependent, with the concentration for half-maximal inhibition being 18 microM. The methoxamine-induced inhibition of IK1 was prevented by bath application of alpha 1-adrenergic blocker prazosin. The current was similarly inhibited by phorbol ester (PMA), an activator of protein kinase C (PKC). In contrast, methoxamine failed to inhibit the current in the presence of a specific PKC inhibitor H-9, suggesting that PKC is involved in the methoxamine-induced inhibition of IK1. In single channel recording from cell-attached patches, bath-applied methoxamine could suppress IK1 channels by decreasing the frequency and duration of bursting without affecting unitary amplitude. Direct application of purified PKC to excised inside-out patches inhibited channel activity similar to methoxamine in cell-attached patches. The PKC selective inhibitor, PKC19-36, prevented the PKC-induced inhibition of the channel. We conclude that human atrial IK1 can be inhibited by alpha 1-adrenergic stimulation via PKC-dependent pathways.
Sato
R
R
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
Koumi
S
S
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D005260:Female; D006325:Heart Atria / Q000166:cytology; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008729:Methoxamine / Q000494:pharmacology*; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C; D008729:Methoxamine