Abstract
To counter the development of salt-sensitive hypertension, multiple brain G-protein-coupled receptor (GPCR) systems are activated to facilitate sympathoinhibition, sodium homeostasis, and normotension. Currently there is a paucity of knowledge regarding the role of down-stream GPCR-activated Gα-subunit proteins in these critically important physiological regulatory responses required for long-term blood pressure regulation. We have determined that brain Gαi2-proteins mediate natriuretic and sympathoinhibitory responses produced by acute pharmacological (exogenous central nociceptin/orphanin FQ receptor (NOP) and α2-adrenoceptor activation) and physiological challenges to sodium homeostasis (intravenous volume expansion and 1 M sodium load) in conscious Sprague–Dawley rats. We have demonstrated that in salt-resistant rat phenotypes, high dietary salt intake evokes site-specific up-regulation of hypothalamic paraventricular nucleus (PVN) Gαi2-proteins. Further, we established that PVN Gαi2 protein up-regulation prevents the development of renal nerve-dependent sympathetically mediated salt-sensitive hypertension in Sprague–Dawley and Dahl salt-resistant rats. Additionally, failure to up-regulate PVN Gαi2 proteins during high salt-intake contributes to the pathophysiology of Dahl salt-sensitive (DSS) hypertension. Collectively, our data demonstrate that brain, and likely PVN specific, Gαi2 protein pathways represent a central molecular pathway mediating sympathoinhibitory renal-nerve dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Further, impairment of this endogenous “anti-hypertensive” mechanism contributes to the pathophysiology of salt-sensitive hypertension.
Highlights
The Department of Pharmacology and Experimental Therapeutics, The Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
To counter the development of salt-sensitive hypertension, multiple brain G-protein-coupled receptor (GPCR) systems are activated to facilitate sympathoinhibition, sodium homeostasis, and normotension
There is a paucity of knowledge regarding the role of down-stream GPCR-activated Gα-subunit proteins in these critically important physiological regulatory responses required for long-term blood pressure regulation
Summary
G-proteins are a family of heterotrimeric proteins composed of α, β, and γ subunits. Following ligand binding at a transmembrane G-protein coupled receptor (GPCR), signal transduction is initiated by α-subunit mediated exchange of GDP for GTP and the dissociation into activated α and βγ complexes that initiate downstream signal transduction to evoke. The final subtype investigated in these studies, Gαq, does not impact cAMP levels, and instead activates phospholipase C (PLC), resulting in increased levels of intracellular inositol triphosphate (IP3) and modulation of calcium release It has been demonstrated in cell culture systems that selective recruitment and/or availability of Gα-subunit proteins plays a critical role in determining the intracellular signaling responses to GPCR activation following ligand binding (Nasman et al, 2001). In vitro studies on the α2-adrenoceptor, an extensively studied key GPCR in cardiovascular regulation, have demonstrated signal transduction via Gαi−, Gαo, Gαs, Gαz, and Gαq subunit proteins which principally modulate adenylate cyclase activity (Remaury et al, 1993; Nasman et al, 2001; Hein, 2006). Despite the elucidation of signal transduction pathways in vitro for the NOP and α2-adrenoceptor (among others), there are essentially no data at present correlating intracellular Gα protein pathways to the physiological responses elicited by central GPCR activation in vivo
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