In rat hepatocytes, atrial natriuretic peptide (ANP) elevates cGMP through activation of particulate guanylyl cyclase and attenuates Ca2+ signals by stimulating net plasma membrane Ca2+ efflux. We show here that ANP-stimulated hepatocyte Ca2+ efflux is mediated by protein kinase G (PKG) isotype I. Furthermore, we show that ANP recruits endogenous PKGI alpha, but not PKGI beta, to the plasma membrane. These effects are mimicked by 8-bromo-cGMP, but not by the soluble guanylyl cyclase activators, sodium nitroprusside and YC-1. We propose that ANP, through localized cGMP elevation, promotes plasma membrane recruitment of PKGI alpha, which, in turn, stimulates Ca2+ efflux. (C) 2008 Elsevier Inc. All rights reserved.