GPCR chemokine or fMet-Leu-Phe Before ligand binding a GPCR is not associated with a G protein Ligand binding causes a conformational change in the receptor which enables it to associate with the G protein G protein dissociates into ˜ and °˛ subunits, both of which can activate other proteins The ˜ subunit cleaves GTP to GDP, allowing the ˜ and °˛ subunits to reassociate Inactive G protein has GDP bound G protein releases GDP and binds GTP Activation of the GTPases Rac, Rho, and Cdc42 stimulates chemotaxis or the respiratory burst Signaling terminates ˜°˛GTP GTP GDP GDP heterotrimeric G protein Rac/Rho Cdc42 Chemotaxis Respiratory burst
Fig. 3.3 G-protein-coupled receptors signal by coupling with intracellular heterotrimeric G proteins. First panel: G-protein-coupled receptors (GPCRs) such as the fMet-Leu-Phe (fMLF) and chemokine receptors signal through GTP-binding proteins known as heterotrimeric G proteins. In the inactive state, the α subunit of the G protein binds GDP and is associated with the β and γ subunits. Second panel: the binding of a ligand to the receptor induces a conformational change that allows the receptor to interact with the G protein, which results in the displacement of GDP and binding of GTP by the α subunit. Third panel: GTP binding triggers the dissociation of the G protein into the α subunit and the βγ subunit, each of which can activate other proteins at the inner face of the cell membrane. In the case of fMLF signaling in macrophages and neutrophils, the α subunit of the activated G protein indirectly activates the GTPases Rac and Rho, whereas the βγ subunit indirectly activates the GTPase Cdc42. The actions of these proteins result in the assembly of the NADPH oxidase, resulting in a respiratory burst. Chemokine signaling acts by a similar pathway and activates chemotaxis. Fourth panel: The activated response ceases when the intrinsic GTPase activity of the α subunit hydrolyzes GTP to GDP, and the α and βγ subunits reassociate. The intrinsic rate of GTP hydrolysis by α subunits is relatively slow, and signaling is regulated by additional GTPase-activating proteins (not shown), which accelerate the rate of GTP hydrolysis.
targets, such as adenylate cyclase, which produces the second messenger cyclic AMP; and phospholipase C, whose activation gives rise to the second messenger inositol 1,3,5-trisphosphate (IP3) and the release of free Ca2+.
Signaling by fMLF and C5a receptors influences cell motility, metabolism, gene expression, and cell division through activation of several Rho family small GTPase proteins. The α subunit of the activated G protein indirectly activates Rac and Rho, while the βγsubunit indirectly activates the small GTPase Cdc42 (see Fig. 3.3). Activation of these GTPases is controlled by guanine nucleotide exchange factors (GEFs) (see Fig. 7.4, which exchange GTP for GDP bound to the GTPase. The G proteins activated by fMLF activate the GEF protein PREX1 (phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein), which can directly activate Rac. Other GEFs, including members of the Vav family that are controlled by other types of receptors (see Section 7-19), can also activate Rac activity, and their activity synergizes with the actions of fMLF and C5a.