Specificity of Receptor–G Protein Coupling: Protein Structure and Cellular Determinants

Neubig, Richard R.

doi:10.1006/smns.1997.0117

Cited by 15 publications

(17 citation statements)

References 73 publications

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“…Although the third intracellular loop of the yeast ␣-factor receptor plays a prominent role in G-protein activation, other GPCR proteins use additional regions of the receptor. In some cases, the second intracellular loop or the C-terminal domain has been implicated in G-protein activation in vitro (6,40,59).…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the C-terminal domain of the ␣-factor receptor plays a role in the transition of the inactive RG complex to the activated state after ligand binding. The C-terminal domains of rhodopsin, adrenergic receptors, and other GPCRs have also been implicated in coupling to the G protein (6,40,59). Moreover, truncations affecting the C-terminal tail of the prostaglandin EP3 receptor have been shown to confer ligand-independent activity (22), indicating that, in this case, the C-terminal domain plays a crucial role in constraining the receptor in its inactive conformation.…”

Section: Discussionmentioning

confidence: 99%

“…We will use the term "preactivation complex" to refer to the complex that forms between unliganded receptor and the G protein (RG). Although this complex is not necessarily a direct intermediate in the formation of the activated ternary complex, it has been proposed that preactivation complexes may play an important role in regulating the specificity and efficiency of G-protein signaling (39,40,52). Although receptor-G-protein complexes have been observed in a few cases (9,35,36,41), the analysis of preactivation and activated complexes has been hampered by the technical limitations of the copurification methods used in these experiments.…”

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confidence: 99%

“…Consequently, most studies have relied on indirect criteria for evaluating the interaction between the R* state and the G protein. These criteria include the ability of mutant receptors to trigger G-protein activation, the ability of G proteins to modulate the affinity of the receptor for its ligand, and the ability of receptor-derived peptides to promote post-receptor signaling events (6,20,40,59). Although these approaches have identified receptor sequences required for G-protein activation, relatively…”

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confidence: 99%

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The C Terminus of the Saccharomyces cerevisiaeα-Factor Receptor Contributes to the Formation of Preactivation Complexes with Its Cognate G Protein

Dosil

Schandel

Gupta

et al. 2000

Molecular and Cellular Biology

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Binding of the ␣-factor pheromone to its G-protein-coupled receptor (encoded by STE2) activates the mating pathway in MATa yeast cells. To investigate whether specific interactions between the receptor and the G protein occur prior to ligand binding, we analyzed dominant-negative mutant receptors that compete with wild-type receptors for G proteins, and we analyzed the ability of receptors to suppress the constitutive signaling activity of mutant G␣ subunits in an ␣-factor-independent manner. Although the amino acid substitution L236H in the third intracellular loop of the receptor impairs G-protein activation, this substitution had no influence on the ability of the dominant-negative receptors to sequester G proteins or on the ability of receptors to suppress the GPA1-A345T mutant G␣ subunit. In contrast, removal of the cytoplasmic C-terminal domain of the receptor eliminated both of these activities even though the C-terminal domain is unnecessary for G-protein activation. Moreover, the ␣-factor-independent signaling activity of ste2-P258L mutant receptors was inhibited by the coexpression of wild-type receptors but not by coexpression of truncated receptors lacking the C-terminal domain. Deletion analysis suggested that the distal half of the C-terminal domain is critical for sequestration of G proteins. The C-terminal domain was also found to influence the affinity of the receptor for ␣-factor in cells lacking G proteins. These results suggest that the C-terminal cytoplasmic domain of the ␣-factor receptor, in addition to its role in receptor downregulation, promotes the formation of receptor-G-protein preactivation complexes.In the yeast Saccharomyces cerevisiae, the ␣-factor pheromone activates a cell-surface receptor on MATa cells, leading to cell division arrest and expression of genes necessary for conjugation (1,16,38). The ␣-factor receptor (encoded by STE2) belongs to the large family of G-protein-coupled receptors (GPCRs), which includes receptors for hormones, neurotransmitters, and sensory stimuli (11, 57). GPCRs transduce their signal by activating a heterotrimeric guanine nucleotide binding protein (G protein) that results in the exchange of GDP for GTP in the G␣ subunit (6,20). In the case of the yeast pheromone pathway, the GTP-bound G␣ subunit releases the G␤␥ subunits, and the free G␤␥ complexes then mediate the subsequent events in the response pathway (1, 16, 38). Although the yeast pheromone receptors and other GPCRs respond to different extracellular signals and share no significant sequence homology, they possess a common structural topology composed of seven transmembrane domains connected by intracellular and extracellular loops. In addition, these receptors exhibit a similar organization of functional domains. For example, as in many GPCRs, the third intracellular loop of the ␣-factor receptor functions in G-protein coupling (10, 58).Moreover, the cytoplasmic C-terminal domain of both yeast and mammalian receptors mediates ligand-induced endocytosis (46, 49) and plays a role in desen...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The C Terminus of the Saccharomyces cerevisiaeα-Factor Receptor Contributes to the Formation of Preactivation Complexes with Its Cognate G Protein

Dosil

Schandel

Gupta

et al. 2000

Molecular and Cellular Biology

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“…In this regard, detailed mutational analysis of different GPCRs has demonstrated the role of this intracellular loop 3 playing a key role in determining receptor-G protein coupling in conjunction with residues present in the intracellular loop 2 [25,137,184]. In the therapeutic context, the 2 -adrenoceptor antagonist mirtazapine is prescribed for the treatment of patients with major depression with positive results [53,54].…”

Section: G Protein-coupled Receptors In Depressed Suicide Brain: Funcmentioning

confidence: 99%

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

González-Maeso

Meana²

2006

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Mood disorders such as major depression and bipolar disorder are common, severe, chronic and often lifethreatening illnesses. Suicide is estimated to be the cause of death in up to approximately 10-15% of individuals with mood disorders. Alterations in the signal transduction through G protein-coupled receptor (GPCR) pathways have been reported in the etiopathology of mood disorders and the suicidal behavior. In this regard, the implication of certain GPCR subtypes such as 2A -adrenoceptor has been repeatedly described using different approaches. However, several discrepancies have been recently reported in density and functional status of the heterotrimeric G proteins both in major depression and bipolar disorder. A compilation of the most relevant research topics about the implication of heterotrimeric G proteins in the etiology of mood disorders (i.e., animal models of mood disorders, studies in peripheral tissue of depressive patients, and studies in postmortem human brain of suicide victims with mood disorders) will provide a broad perspective of this potential therapeutic target field. Proposed causes of the discrepancies reported at the level of G proteins in postmortem human brain of suicide victims will be discussed.

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Overview of Receptor Allosterism

2000

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Studies of the behavior of many ligand‐gated ion channels have long provided evidence that more than one molecule of ligand was able to bind to each receptor complex, a phenomenon termed cooperativity. The conclusion that some receptors possessed more than one binding site for ligands thus invoked another phenomenon that was originally described in the field of enzymology, that is, the concept of allosteric binding sites. The biological activity of enzymes can be modified, either in a positive or negative fashion, by the binding of ligands to sites that are topographically distinct from the substrate‐binding site. These accessory binding sites are termed allosteric sites, in contrast to the substrate‐binding (active) site (the isosteric site). Thus, allosteric interactions arise because the binding of a ligand to the allosteric site induces a conformational change in the protein that modulates the binding of the substrate to the isosteric site, and vice versa. The biological activity of the enzyme arises from the subsequent (modified) properties of the substrate‐binding site, and not through a direct effect of the allosteric modulator itself. This overview unit discusses definitions of various terms used in the field of receptor allosterism, and explains in clear terms how allosteric transitions and interactions can affect receptor activation. In addition, the functions of allosteric modulators are discussed along with explanations of how these modulators can be attractive tools for drug development.

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Specificity of Receptor–G Protein Coupling: Protein Structure and Cellular Determinants

Cited by 15 publications

References 73 publications

The C Terminus of the Saccharomyces cerevisiaeα-Factor Receptor Contributes to the Formation of Preactivation Complexes with Its Cognate G Protein

The C Terminus of the Saccharomyces cerevisiaeα-Factor Receptor Contributes to the Formation of Preactivation Complexes with Its Cognate G Protein

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

Overview of Receptor Allosterism

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