The protein kinase domain of the ANP receptor is required for signaling.
A plasma membrane form of guanylate cyclase is a cell surface receptor for atrial natriuretic peptide (ANP). In response to ANP binding, the receptor-enzyme produces increased amounts of the second messenger, guanosine 3',5'-monophosphate. Maximal activation of the cyclase requires the presence of adenosine 5'-triphosphate (ATP) or nonhydrolyzable ATP analogs. The intracellular region of the receptor contains at least two domains with homology to other proteins, one possessing sequence similarity to protein kinase catalytic domains, the other to regions of unknown function in a cytoplasmic form of guanylate cyclase and in adenylate cyclase. It is now shown that the protein kinase-like domain functions as a regulatory element and that the second domain possesses catalytic activity. When the kinase-like domain was removed by deletion mutagenesis, the resulting ANP receptor retained guanylate cyclase activity, but this activity was independent of ANP and its stimulation by ATP was markedly reduced. A model for signal transduction is suggested in which binding of ANP to the extracellular domain of its receptor initiates a conformational change in the protein kinase-like domain, resulting in derepression of guanylate cyclase activity.
Chinkers
M
M
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Garbers
D L
DL
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology; D004252:DNA Mutational Analysis; D006162:Guanylate Cyclase / Q000378:metabolism; D008274:Magnesium / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000502:physiology* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D014162:Transfection
D011956:Receptors, Cell Surface; D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP; D008274:Magnesium