G proteins in the heart. A redundant and diverse transmembrane signaling network.

G proteins, or GTP-binding proteins, are a family of proteins that act as links in signaling chains across cell membranes in all eukaryotic cells.1-3 These pathways usually include a receptor molecule, a G protein as the signal transducer, and an effector enzyme or ion channel that can be activated or inhibited by the G protein. A large variety of stimuli reaching the cell surface, including numerous neurohumoral and olfactory signals and light, can be transmitted by these specific signaling mechanisms. It is remarkable that this diversity of signals is processed by structurally similar transducing mechanisms, including the activation of a GTP-binding protein. From sequence and structure analyses, we know that receptors that transduce a signal through the activation of a G protein share a common structure consisting of seven transmembrane-spanning domains, intracellular and extracellular loops, an extracellular amino terminus, and a cytoplasmic carboxy terminus.3 The cytoplasmic loops, particularly the third cytoplasmic loop, and the carboxy terminus appear to be involved in G protein coupling. G proteins also share a common structure, which is heterotrimeric, consisting of an a!,B/ y-subunit; the a-subunit is thought to be responsible for the specific action by directly interacting with the effector. In addition, the a-subunit binds and subsequently hydrolyzes GTP, the important events that first activate and then deactivate the G protein. Since the first evidence of a GTP-dependent step in the activation of adenylyl cyclase in 19714 and the following purification and characterization of a GTPbinding protein as a regulator of adenylyl cyclase,5 now called Gs, at least 15 G protein a-subunits have been discovered, and this number is still increasing. An inhibitory G protein, termed Gi, has been shown to inhibit adenylyl cyclase activity.67 At least three iso-