SELECTIVELY ENHANCED CELLULAR SIGNALING BY G(I) PROTEINS IN ESSENTIAL-HYPERTENSION - G-ALPHA(I2), G-ALPHA(I3), G-BETA(1), AND G-BETA(2) ARENOT MUTATED

Recent studies have shown an enhanced signaling capacity of receptors coupled to pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G proteins) in immortalized B lymphoblasts from patients wit h essential hypertension. In the present study, we analyzed (1) whethe r such alterations would also be expressed in nontransformed cells of these individuals and (2) whether other G protein-mediated signaling p athways were also altered. Therefore, we established primary cultures of skin fibroblasts from previously characterized normotensive and hyp ertensive individuals (NT and HT cells, respectively). [Ca2+], rises i nduced by lyso-phosphatidic acid (LPA), thrombin, and sphingosine-1-ph osphate as well as the formation of inositol 1,4,5-trisphosphate and [ H-3]thymidine incorporation evoked by LPA were PTX sensitive and enhan ced twofold in HT fibroblasts. In contrast, cellular responses induced by bradykinin, endothelin-1, and angiotensin II (all PTN insensitive) were similar in NT and HT cells. Formation of cAMP induced by stimula tion of G, with isoproterenol was identical in NT and HT cells. Wester n blot analysis yielded no evidence for an overexpression of G alpha(1 2), G alpha(13), G beta(2), and G beta(4). Furthermore, sequencing of cDNAs encoding for the ubiquitously expressed PTX-sensitive G protein subunits G alpha(12), G alpha(13), G beta 1 and G beta(2) from NT and HT cell lines yielded no evidence for mutations in these genes. Althou gh the molecular mechanisms remain to be defined, these data support t he concept of a selective enhancement of signal transduction via PTX-s ensitive G proteins in essential hypertension.