Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation.
Natriuretic peptides inhibit the release and action of many hormones through cyclic guanosine monophosphate (cGMP), but the mechanism of cGMP action is unclear. In frog ventricular muscle and guinea-pig hippocampal neurons, cGMP inhibits voltage-activated Ca2+ currents by stimulating phosphodiesterase activity and reducing intracellular cyclic AMP; however, this mechanism is not involved in the action of cGMP on other channels or on Ca2+ channels in other cells. Natriuretic peptide receptors in the rat pituitary also stimulate guanylyl cyclase activity but inhibit secretion by increasing membrane conductance to potassium. In an electrophysiological study on rat pituitary tumour cells, we identified the large-conductance, calcium- and voltage-activated potassium channels (BK) as the primary target of another inhibitory neuropeptide, somatostatin. Here we report that atrial natriuretic peptide also stimulates BK channel activity in GH4C1 cells through protein dephosphorylation. Unlike somatostatin, however, the effect of atrial natriuretic peptide on BK channel activity is preceded by a rapid and potent stimulation of cGMP production and requires cGMP-dependent protein kinase activity. Protein phosphatase activation by cGMP-dependent kinase could explain the inhibitory effects of natriuretic peptides on electrical excitability and the antagonism of cGMP and cAMP in many systems.
White
R E
RE
Laboratory of Cellular and Molecular Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Lee
A B
AB
Shcherbatko
A D
AD
Lincoln
T M
TM
Schonbrunn
A
A
Armstrong
D L
DL
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D018999:Charybdotoxin; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010911:Pituitary Neoplasms; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004988:Ethers, Cyclic; D015221:Potassium Channels; D012604:Scorpion Venoms; D013757:Tetraethylammonium Compounds; D013873:Thionucleotides; D018999:Charybdotoxin; D019319:Okadaic Acid; C016276:8-bromocyclic GMP; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D019789:Tetraethylammonium; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases; D006152:Cyclic GMP