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FIGURE 1–2. G protein–coupled receptors and G protein activation.

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FIGURE 1–2. G protein–coupled receptors and G protein activation.All G proteins are heterotrimers consisting of , , and subunits. The receptor shuttles between a low-affinity form that is not coupled to a G protein and a high-affinity form that is coupled to a G protein. (A) At rest, G proteins are largely in their inactive state, namely, as heterotrimers, which have GDP (guanosine diphosphate) bound to the subunit. (B) When a receptor is activated by a neurotransmitter, it undergoes a conformational (shape) change, forming a transient state referred to as a high-affinity ternary complex, comprising the agonist, receptor in a high-affinity state, and G protein. A consequence of the receptor interaction with the G protein is that the GDP comes off the G protein subunit, leaving a very transient empty guanine nucleotide binding domain. (C) Guanine nucleotides (generally GTP) quickly bind to this nucleotide binding domain; thus, one of the major consequences of active receptor–G protein interaction is to facilitate guanine nucleotide exchange—this is basically the "on switch" for the G protein cycle. (D) A family of GTPase-activating proteins for G protein–coupled receptors has been identified, and they are called regulators of G protein signaling (RGS) proteins. Since activating GTPase activity facilitates the "turn off" reaction, these RGS proteins are involved in dampening the signal. Binding of GTP to the subunit of G proteins results in subunit dissociation, whereby the -GTP dissociates from the subunits. Although not covalently bound, the and subunits remain tightly associated and generally function as dimers. The -GTP and subunits are now able to activate multiple diverse effectors, thereby propagating the signal. While they are in their active states, the G protein subunits can activate multiple effector molecules in a "hit and run" manner; this results in major signal amplification (i.e., one active G protein subunit can activate multiple effector molecules; see Figure 1–11). The activated G protein subunits also dissociate from the receptor, converting the receptor to a low-affinity conformation and facilitating the dissociation of the agonist from the receptor. The agonist can now activate another receptor, and this also results in signal amplification. Together, these processes have been estimated to produce a 10,000-fold amplification of the signal in certain models. (E) Interestingly, the subunit has intrinsic GTPase activity, which cleaves the third phosphate group from GTP (G-P-P-P) to GDP (G-P-P). Since -GDP is an inactive state, the GTPase activity serves as a built-in timing mechanism, and this is the "turn off" reaction. (F) The reassociation of -GDP with is thermodynamically favored, and the reformation of the inactive heterotrimer () completes the G protein cycle.

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