Figure 15–22 The structure of an inactive G protein. (A) Note that both the α and the γ subunits have covalently attached lipid molecules (red tails) that help bind them to the plasma membrane, and the α subunit has GDP bound. (B) The three-dimensional structure of the inactive, GDP-bound form of a G protein called Gs, which interacts with numerous GPCRs, including the  β2-adrenergic receptor shown in Figures 15–21 and 15–23. The α subunit contains the GTPase domain and binds to one side of the β subunit. The γ subunit binds to the opposite side of the β subunit, and the β and γ subunits together form a single functional unit. The GTPase domain of the α subunit contains two major subdomains: the “Ras” domain, which is related to other GTPases and provides one face of the nucleotide-binding pocket; and the alpha-helical or “AH” domain, which clamps the nucleotide in place. (B, based on
D.G. Lombright et al., Nature 379:311– 319, 1996. With permission from Macmillan Publishers Ltd.)
Figure 15–23 Activation of a G protein by an activated GPCR. Binding of an extracellular signal molecule to a GPCR changes the conformation of the receptor, which allows the receptor to bind and  alter the conformation of a trimeric G protein. The AH domain of the G protein α subunit moves outward to open the nucleotide-binding site, thereby promoting dissociation of GDP. GTP binding then promotes closure of the nucleotide-binding site, triggering conformational changes that cause dissociation of the α subunit from the receptor and from the βγ complex. The GTP-bound α subunit and the βγ complex each regulate the activities of downstream signaling molecules (not shown). The receptor stays active while the extracellular signal molecule is bound to it, and it can therefore catalyze the activation of many G-protein molecules (Movie 15.1).
adenylyl cyclase, and it is rapidly and continuously destroyed by cyclic AMP phosphodiesterases (Figure 15–25). Adenylyl cyclase is a large, multipass trans-membrane protein with its catalytic domain on the cytosolic side of the plasma membrane. There are at least eight isoforms in mammals, most of which are regulated by both G proteins and Ca2+.
Many extracellular signals work by increasing cAMP concentrations inside the cell. These signals activate GPCRs that are coupled to a stimulatory G protein (Gs). The activated α subunit of Gs binds and thereby activates adenylyl cyclase. Other extracellular signals, acting through different GPCRs, reduce cAMP levels by activating an inhibitory G protein (Gi), which then inhibits adenylyl cyclase.