Gα q-coupled receptors such as α 1-adrenergic, angiotensin, and endothelin receptors, play key roles in cardiac physiology. These receptors have also been shown to couple to G proteins of the G 12 family, including Gα 12 and Gα 13. In this report, we determined whether these G proteins interact with endothelin, angiotensin, and α 1-adrenergic receptors in the human heart. We find that these receptors activate cardiac Gα 12 and Gα 13 differentially; endothelin receptors activate only Gα 12 (to 218±22% of unstimulated levels), angiotensin receptors activate only Gα 13 (to 236±49% of unstimulated levels), and α 1-adrenergic receptors activate neither Gα 12 (123±18% of unstimulated levels) nor Gα 13 (113±12% of unstimulated levels). Consistent with these data, translocation of guanine nucleotide exchange factor p115RhoGEF, which responds to Gα 13, occurs only after stimulation of angiotensin receptors (shifting from 73±12% to 41±10% cytosolic). These differences in the activation of Gα 12 and Gα 13 by Gα q-coupled receptors may underlie reported differences in the functions of these receptors.