Identification of G protein-coupled signaling pathways in cardiac fibroblasts: cross talk between G(q) and G(s)

Cardiac fibroblasts (CFs) are an important cellular component of myocardial responses to injury and to hypertrophic stimuli. We studied G protein-coup led receptors to understand how CFs integrate signals that activate G(q), G (s), and G(i). We predicted that the second messenger pathways present in C Fs were distinct from those in cardiac myocytes and that unique signaling i nteractions existed in the CFs. ANG II, bradykinin, ATP, and UTP stimulated inositol phosphate (IP) production 2.2- to 7-fold. Each of these agonists elevated intracellular Ca2+ concentration([Ca2+](i)) via release from the i ntracellular Ca2+ storage compartment. Endothelin-1 (ET-1), carbachol, and norepinephrine failed to increase either IP production or [Ca2+](i). Althou gh agonists that activated IP and Ca2+ transients had no effect on cAMP pro duction when administered alone, these agents potentiated the beta(2)-adren ergic response two- to fourfold. Hormones known to inhibit adenylyl cyclase activity in cardiac myocytes, such as ET-1 and carbachol, failed to lower the beta-adrenergic response in fibroblasts. Order of potency and inhibitor data indicate that the functional receptor subtypes in these cells are bet a(2), P2Y(2), and AT(1) for isoproterenol, ATP, and ANG II, respectively. W e conclude that CFs express functional G protein-linked receptors that coup le to G(q) and G(s), with little or no coupling to G(i). The expression of receptors and their coupling to G(q)- but not to G(i)-linked responses dist inguishes the signaling in CFs from that in myocytes. Furthermore, agonists that activate G(q) in CFs potentiate stimulation of G(s), an example of si gnaling cross talk not observed in adult myocytes. These data suggest that G protein-mediated signaling in CFs is unique and may contribute to the spe cificity of hormone and drug action on individual cell types within the hea rt.