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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 «tW 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 K-GDP with D"f is thermodynamically favored, and the reformation of the inactive heterotrimer (otrs"f) completes the G protein cycle.

Homologous desensitization is receptor specific; that is, only the receptor actively being stimulated becomes desensitized. This form of desensitization occurs via a family of kinases known as G protein-coupled kinases (GRKs). When a receptor activates a G protein and causes dissociation of the* subunit from the subunits (discussed in detail later), the PI subunits are able to provide an "anchoring surface" for the GRKs to allow them to come into the proximity of the activated receptor and phosphorylate it. This phorphorylation then recruits another family of proteins known as arrestins, which physically interfere with the coupling of the phosphorylated receptor and the G protein, thereby dampening the signal. This form of desensitization is very rapid and usually transient (i.e., the receptors get dephosphorylated and return to the baseline state). However, if the stimulation of the receptor is excessive and prolonged, it leads to an internalization of the receptor, and often its degradation, a process referred to as downregulation.

Heterologous desensitization is not receptor specific and is mediated by second-messenger kinases such as protein kinase A (PKA) and protein kinase C (PKC). Thus, when a receptor activates PKA, the activated PKA is capable of phosphorylating (and thereby desensitizing) not only that particular receptor but also other receptors that are present in proximity and have the correct phosphorylation motif, thereby producing heterologous desensitization.

Upon prolonged or repeated activation of receptors by agonist ligands, the process of receptor downregulation is observed. Downregulation is associated with a reduced number of receptors detected in cells or tissues, thereby leading to attenuation of cellular responses (Carman and Benovic 1998). The process of GPCR sequestration is mediated by a well-characterized endocytic pathway involving the concentration of receptors in clathrin-coated pits and subsequent internalization and recycling back to the plasma membrane (Tsao and von Zastrow 2000). Endocytosis can thus clearly serve as a primary mechanism to attenuate signaling by rapidly and reversibly removing receptors from the cell surface. However, emerging evidence suggests additional functions of endocytosis and receptor trafficking in mediating GPCR signaling by way of certain effector pathways, most notably mitogen-activated protein (MAP) kinase cascades (discussed in greater detail later). There is also evidence that endocytosis of GPCRs may be required for certain signal transduction pathways leading to the nucleus (Tsao and von Zastrow 2000). These diverse functions of GPCR endocytosis and trafficking are leading to unexpected insights into the biochemical and functional properties of endocytic vesicles. Indeed, there is considerable excitement about our growing understanding of the diverse molecular mechanisms for signaling specificity and receptor trafficking, and the possibility that this knowledge could lead to highly selective therapeutics.

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