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-coupled 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 CFs were distinct from those in cardiac myocytes and that unique signaling interactions 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 Ca(2+) concentration ([Ca(2+)](i)) via release from the intracellular Ca(2+) storage compartment. Endothelin-1 (ET-1), carbachol, and norepinephrine failed to increase either IP production or [Ca(2+)](i). Although agonists that activated IP and Ca(2+) transients had no effect on cAMP production when administered alone, these agents potentiated the beta(2)-adrenergic 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 beta(2), P2Y(2), and AT(1) for isoproterenol, ATP, and ANG II, respectively. We conclude that CFs express functional G protein-linked receptors that couple 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 distinguishes the signaling in CFs from that in myocytes. Furthermore, agonists that activate G(q) in CFs potentiate stimulation of G(s), an example of signaling cross talk not observed in adult myocytes. These data suggest that G protein-mediated signaling in CFs is unique and may contribute to the specificity of hormone and drug action on individual cell types within the heart.
Meszaros
J G
JG
Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, California 92093-0636, USA. jmeszaros@ucsd.edu
Gonzalez
A M
AM
Endo-Mochizuki
Y
Y
Villegas
S
S
Villarreal
F
F
Brunton
L L
LL
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013566:Sympathomimetics / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D019332:Endothelin-1; D013566:Sympathomimetics; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002217:Carbachol; D000242:Cyclic AMP; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs; D006152:Cyclic GMP; D007545:Isoproterenol; D001920:Bradykinin; D002118:Calcium; D014544:Uridine Triphosphate; D009638:Norepinephrine