GTP-binding proteins are activated by GTP binding, while hydrolysis of GTP to GDP inactivates them. Regulatory proteins, such as GTPase-activating proteins (GAP) and guanine nucleotide exchange factors (GEF), control the activity of GTPases. GAP induces the hydrolysis of GTP to GDP, leading to inactivation of the GTPase, while GEF causes the release of GDP and its replacement by GTP, thereby activating the GTPase. Ras GTPases play a role in signaling pathways related to cell division, proliferation, and death. Arf GTPases, like Rab GTPases, regulate vesicular transport.

Heterotrimeric G proteins are linked to over 1000 receptors, enabling the cellular response to a wide range of signaling molecules including hormones, neurotransmitters, peptides, and odorants. These proteins can be membrane-bound due to the addition of lipids posttranslationally. Heterotrimeric complexes consist of three subunits: α, β, and γ. There are 16 α subunits, 5 β subunits, and 11 γ subunits, which can assemble in various combinations to interact with different receptors and effectors. The specific assembly and association of subunits with receptors and effectors depend on the cell type.

The activation of heterotrimeric G proteins is illustrated in Figure 3.9. In the absence of ligand, these proteins are inactive and form a heterotrimeric complex with GDP bound to the α subunit. When a signal molecule binds to an inactive GPCR, it induces a conformational change in the G protein, leading to the release of GDP and the binding of GTP to the α subunit. This binding of GTP stimulates dissociation of the α subunit from the heterotrimeric complex, resulting in the release of the α subunit from the βγ dimer. Both the α subunit and βγ dimer can then interact with downstream effectors such as adenylyl cyclase and phospholipases. The activation of downstream effectors by the α subunit and βγ dimer is terminated when the α subunit hydrolyzes GTP to GDP and inorganic phosphate (Pi). The α subunit, now bound to GDP, associates with the βγ dimer, thus ending the activation of effectors.

Another mechanism to attenuate or terminate signaling through a GPCR involves desensitization and endocytic removal of receptors from the plasma membrane. Binding of a hormone to a GPCR enhances the ability of GPCR kinases to phosphorylate the intracellular domain of GPCRs. This phosphorylation recruits β-arrestins, which bind to the GPCR, inactivating it and promoting endocytosis.
• Fig. 3.8 GTP-Binding Proteins. GTP binding activates whereas hydrolysis of GTP to GDP inactivates GTP-binding proteins (A). All GTPase are controlled by regulatory proteins, including GTPase-activating proteins (GAP), which induce the hydrolysis of GTP to GDP, thus inactivating the GTPase, and guanine nucleotide exchange factors, (GEF) that which cause the GTPase to release GDP, which is rapidly replaced by GTP, thereby activating the GTPase (B). (Redrawn from Kantrowitx ER, Lipscomb WN. Escherichia coli aspartate transcarbamoylase: the molecular basis for a concerted allosteric transition. Trends Biochem
Sci. 1990;15:53-59.) proteins. Ras GTPases are involved in many signaling pathways that control cell division, proliferation and death. Arf GTPases, like Rab GTPases, regulate vesicular transport.
Heterotrimeric G proteins couple to more than 1000 different receptors and thereby mediate the cellular response to an incredibly diverse set of signaling molecules, including hormones, neurotransmitters, peptides, and odorants. Like monomeric G proteins, they can be membrane bound because of the addition of lipids posttranslationally. Heterotrimeric complexes are composed of three subunits: α, β, and γ. There exist 16 α subunits, 5 β subunits, and 11 γ subunits, which can assemble into hundreds of different combinations and thereby interact with a diverse number of receptors and effectors. The assembly of subunits and the association with receptors and effectors depend on the cell type.
An overview of heterotrimeric G protein activation is illustrated in
Fig. 3.9 . In the absence of ligand, these G proteins are inactive and form a heterotrimeric complex in which GDP binds to the α subunit. Binding of a signal molecule to an inactive GPCR induces a conformational change in the G protein that promotes the release of GDP and the subsequent binding of GTP to the α subunit. Binding of GTP to the α subunit stimulates dissociation of the α subunit from the heterotrimeric complex and results in release of the α subunit from the βγ dimer, each of which can interact with and regulate downstream effectors such as adenylyl cyclase and phospholipases (see
Fig. 3.9 ). Activation of downstream effectors by the α subunit and βγ dimer is terminated when the α subunit hydrolyzes the bound GTP to GDP and inorganic phosphate (Pi). The α subunit bound to GDP associates with the βγ dimer and terminates the activation of effectors.
Another way to attenuate or terminate signaling through a GPCR involves desensitization and endocytic removal of receptors from the plasma membrane. Binding of hormone to a GPCR increases the ability of GPCR kinases to phosphorylate the intracellular domain of GPCRs, which recruits proteins called β-arrestins to bind to the GPCR. β-Arrestins inactivate the receptor and promote endocytic