Guanosine 5'-monophosphate modulates gating of high-conductance Ca2+-activated K+ channels in vascular smooth muscle cells.
Ca2+-activated K+ channels (PKCa channels) account for the predominant K+ permeability of many types of smooth muscle cells. When activated, they oppose depolarization due to Na+ and Ca2+ channel activity. Several vasodilatory agents that increase intracellular cGMP levels (e.g., nitroprusside, adenosine, and atrial natriuretic factor) enhance the activity of these high-conductance PKCa channels in on-cell patches of bovine aortic smooth muscle cells. In addition, dibutyryl-cGMP (1.0 mM) causes a similar increase in channel activity. To pursue the mechanism of channel modulation by these agents, a series of guanine and adenine nucleotides were evaluated by using inside-out excised patches. Whereas cAMP, AMP, ADP, and ATP were ineffective, all of the corresponding guanine nucleotides potentiated PKCa channel activity when tested at a high concentration (500 microM). However, only GMP consistently enhanced channel activity in the 1-100 microM range by increasing the percent open time and frequency of opening of these channels over a wide range of potentials and Ca2+ levels without affecting single-channel conductance. Thus, GMP is a potent modulator of PKCa channels and it, rather than cGMP, may mediate the action of the vasodilators examined in this study.
Williams
D L
DL
Department of Biological Chemistry, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Katz
G M
GM
Roy-Contancin
L
L
Reuben
J P
JP
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D004357:Drug Synergism; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006157:Guanosine Monophosphate / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D006150:Guanine Nucleotides; D015221:Potassium Channels; D014665:Vasodilator Agents; D003995:Dibutyryl Cyclic GMP; D006157:Guanosine Monophosphate; D002118:Calcium