Natriuretic peptides inhibit G protein activation. Mediation through cross-talk between cyclic GMP-dependent protein kinase and regulators of G protein-signaling proteins.
Atrial natriuretic peptide (ANP) inhibits the proliferation of many cells, in part through interfering with signal transduction enacted by G protein-coupled growth factor receptors. Signaling interactions between ANP and the G protein-coupled growth factor receptor ligand, endothelin-3 (ET-3), regulate astrocyte proliferation at a very proximal but undefined point. Here, we find that ANP inhibits the ability of ET-3 to activate Galpha(q) and Galpha(i) in these cells. ANP stimulated the translocation of endogenous regulators of G protein-signaling (RGS) proteins 3 and 4 from the cytosol to the cell membrane, and enhanced their association with Galpha(q) and Galpha(i). ANP effects were significantly blocked by HS-142-1, an inhibitor of guanylate cyclase activation, or by ET-3. KT5823, an inhibitor of cyclic GMP-dependent protein kinase (PKG) reversed the RGS translocation induced by ANP; conversely, expression of an active catalytic subunit of PKG-I, or 8-bromo-cyclic GMP stimulated RGS translocation. ANP caused the phosphorylation of both RGS proteins in a PKG-dependent fashion, and the expressed PKG (in the absence of ANP) also stimulated RGS phosphorylation. A novel cross-talk between PKG and RGS proteins is stimulated by ANP and leads to the increased translocation and association of RGS proteins with Galpha. The rapid inactivation of G proteins provides a mechanism by which ANP inhibits downstream signaling to the cell proliferation program.
Pedram
A
A
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, California 90822, USA.
Razandi
M
M
Kehrl
J
J
Levin
E R
ER
D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001692:Biological Transport; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D019334:Endothelin-3 / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D020710:RGS Proteins / Q000502:physiology*
D019334:Endothelin-3; D020710:RGS Proteins; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins