Structure and Function of G Protein-Coupled Receptors

Strader, Catherine D.; Fong, Tung M.; Tota, Michael R.; Underwood, Dennis; Dixon, Richard A. F.

doi:10.1146/annurev.bi.63.070194.000533

Cited by 1,011 publications

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“…Neuropeptides exert their cellular e ects by binding to G-protein-coupled receptors (GPCRs), a large and diverse superfamily of proteins characterized by a seven-transmembrane structure (Gudermann et al, 1997;SchoÈ neberg et al, 1999;Strader et al, 1994). Agonist-bound neuropeptide receptors transmit information into the cell by activating regulatory guanine nucleotide-binding proteins (G proteins) composed of a, b, and g subunits.…”

Section: Introductionmentioning

confidence: 99%

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

et al. 2000

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Neuropeptides like galanin produced and released by small cell lung cancer (SCLC) cells are considered principal mitogens in these tumors. We identi®ed the galanin receptor type 2 (GALR2) as the only galanin receptor expressed in H69 and H510 cells. Photoa nity labeling of G proteins in H69 cell membranes revealed that GALR2 activates G proteins of three subfamilies: G q , G i , and G 12 . In H69 cells, galanin-induced Ca 2+ mobilization was pertussis toxin-insensitive. While phorbol ester-induced extracellular signal-regulated kinase (ERK) activation required protein kinase C (PKC) activity, preincubation of H69 cells with the PKCinhibitor GF109203X had no e ect on galanin-dependent ERK activity. A rise of the intracellular calcium concentration was necessary and su cient to mediate galanin-induced ERK activation. In support of G i coupling, stimulation of GALR2 expressed in HEK293 cells inhibited isoproterenol-induced cAMP accumulation and raised cAMP levels in COS-7 cells when coexpressed with a chimeric Ga S -Ga i protein. In H69 cells, galanin activated the monomeric GTPase RhoA and induced stress ®ber formation in Swiss 3T3 cells expressing GALR2. Thus, we provide the ®rst direct evidence that in SCLC the mitogenic neuropeptide galanin, interacting with GALR2, simultaneously activates multiple classes of G proteins and signals through the G q phospholipase C/calcium sequence and a G 12 /Rho pathway. Oncogene (2000) 19, 4199 ± 4209.

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Section: Introductionmentioning

confidence: 99%

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

et al. 2000

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“…Molecular cloning of these seventransmembrane-domain receptors has revealed a large gene family with many common structural features [3][4][5]. The presence of some partially conserved regions in the sequences of members of this gene family has permitted the use of homologous screening and polymerase chain reaction (PCR) amplification to isolated novel receptors [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Cloning, sequencing and tissue distribution of two related G protein‐coupled receptor candidates expressed prominently in human lung tissue

Tsai

Goetzl

1995

FEBS Letters

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A novel G protein-coupled receptor, named GPR12A, was cloned by a PCR strategy using degenerate primers designed from sequences conserved among receptors for inflammatory mediators. Screening of a human lung cDNA library with GPR12A as a probe also identified a closely-related cDNA (GPR6C.1) that has been previously reported as GPR4 [13]. GPR12A and GPR6C.1 are 46.1% identical in amino acid sequence, but are less than 33% identical to any other known receptors. Northern analysis revealed that they are expressed prominently in the lung. Although the ligands for GPR12A and GPR6C.1 are unknown, their similarity suggests that they are receptors for ligands of similar or identical chemical nature.

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“…G protein-coupled receptors (GPCRs), 1 when activated by extracellular ligands, interact with specific classes of heterotrimeric G proteins (consisting of ␣, ␤, and ␥ subunits) which can then, in their activated forms, inhibit or activate various effector enzymes and/or ion channels (1)(2)(3)(4)(5). Characteristically, a specific GPCR can interact with only a limited subset of the many structurally similar G proteins that are expressed within a cell.…”

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confidence: 99%

The N-terminal Extension of Gαq Is Critical for Constraining the Selectivity of Receptor Coupling

Kostenis

Degtyarev²,

Conklin³

et al. 1997

Journal of Biological Chemistry

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Characteristically, an individual member of the superfamily of G protein-coupled receptors can interact only with a limited number of the many structurally closely related G protein heterotrimers that are expressed within a cell. Interestingly, the N termini of two G protein ␣ subunits, G␣ q and G␣ 11 , differ from those of other ␣ subunits in that they display a unique, highly conserved six-amino acid extension. To test the hypothesis that this sequence element is critical for proper receptor recognition, we prepared a G␣ q deletion mutant (؊6q) lacking these first six amino acids. The ؊6q construct (or wild type G␣ q as a control) was coexpressed (in COS-7 cells) with several different G i/o -or G s -coupled receptors, and ligand-induced increases in inositol phosphate production were determined as a measure of G protein activation. Whereas these receptors did not efficiently interact with wild type G␣ q , most of them gained the ability to productively couple to ؊6q. Additional experiments indicated that the observed functional promiscuity of ؊6q is not due to overexpression (as compared with wild type G␣ q ) or to a lack of palmitoylation. We conclude that the N-terminal extension characteristic for G␣ q/11 proteins is critical for constraining the receptor coupling selectivity of these subunits, indicative of a novel mechanism by which the fidelity of receptor-G protein interactions can be regulated.G protein-coupled receptors (GPCRs), 1 when activated by extracellular ligands, interact with specific classes of heterotrimeric G proteins (consisting of ␣, ␤, and ␥ subunits) which can then, in their activated forms, inhibit or activate various effector enzymes and/or ion channels (1-5). Characteristically, a specific GPCR can interact with only a limited subset of the many structurally similar G proteins that are expressed within a cell. Molecular genetic and biochemical studies have identified distinct intracellular regions (as well as single amino acids contained within these domains) on the GPCR proteins that play key roles in determining the fidelity of receptor-G protein coupling (1-7). In addition, recent studies have shown that residues at the extreme C terminus of the G protein ␣ subunits are also of fundamental importance for the selectivity of receptor-G protein interactions (8 -10). However, several lines of evidence suggest that the C terminus of the G␣ subunits is clearly not the only structural determinant on the G proteins that is critical for dictating receptor-G protein coupling selectivity (2, 5).Interestingly, two G protein ␣ subunits, G␣ q and G␣ 11 , contain a unique six-amino acid extension that is not found in other G␣ subunits (Fig. 1). This short sequence is highly conserved among all vertebrate species from which these subunits have been cloned so far (11)(12)(13)(14)(15), suggesting that it may be relevant for some aspect of G␣ q /G␣ 11 function.Previous studies (16,17) analyzing the biochemical properties of a mutant G␣ q subunit lacking the N-terminal extension (hereafter referred...

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Structure and Function of G Protein-Coupled Receptors

Cited by 1,011 publications

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The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to Gq, Gi and G12 proteins

Cloning, sequencing and tissue distribution of two related G protein‐coupled receptor candidates expressed prominently in human lung tissue

The N-terminal Extension of Gαq Is Critical for Constraining the Selectivity of Receptor Coupling

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