Model Systems for the Study of Seven-Transmembrane-Segment Receptors

Dohlman, Henrik G.; Thorner, Jeremy; Caron, Marc G.; Lefkowitz, Robert J.

doi:10.1146/annurev.bi.60.070191.003253

Cited by 1,320 publications

(609 citation statements)

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“…Receptors such as β-adrenergic receptors are down-regulated by a specific receptor kinase. The slow phase of desensitization frequently involves receptor internalization [18,19]. P #Y receptors in turkey erythrocytes coupled to phospholipase C have already been shown to be desensitized owing to a modification at the receptor level [14].…”

Section: Discussionmentioning

confidence: 99%

Desensitization of P2U receptor in neuronal cell line. Different control by the agonists ATP and UTP, as demonstrated by single-cell Ca2+ responses

Czubayko

Reiser

1996

Biochemical Journal

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The neuronal cell line NG108-15 (180CC15) responds to extracellular stimuli of ATP or UTP with a transient increase in the level of cytosolic Ca# + . Desensitization was investigated by recording single-cell Ca# + responses induced by consecutive, regularly spaced (100 s intervals), brief pulses of the nucleotides. The two natural ligands of the P #U receptor, ATP and UTP, were applied at a concentration that evoked responses of a comparable size. With two pulses of UTP (10 µM), a substantial decrease (of 43 %) was observed in the size of the second response. The magnitude of response was determined by measuring either the maximal amplitude or the total response, represented by the area of the Ca# + transient. The analogous studies with ATP pulses showed a much smaller decrease (of 12 %). Comparable experiments performed to investigate the mutual interaction between ATP and UTP revealed that after stimulation with ATP the

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Section: Discussionmentioning

confidence: 99%

Desensitization of P2U receptor in neuronal cell line. Different control by the agonists ATP and UTP, as demonstrated by single-cell Ca2+ responses

Czubayko

Reiser

1996

Biochemical Journal

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“…G protein-coupled receptors mediate cellular responses elicited by a variety of extracellular stimuli ranging from photons, odorants and ions to neurotransmitters, regulatory peptides and bioactive lipids [1,2]. Molecular cloning of these seventransmembrane-domain receptors has revealed a large gene family with many common structural features [3][4][5].…”

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.…”

mentioning

confidence: 99%

“…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)(2)(3)(4)(5)(6)(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).…”

mentioning

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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Model Systems for the Study of Seven-Transmembrane-Segment Receptors

Cited by 1,320 publications

References 1 publication

Desensitization of P2U receptor in neuronal cell line. Different control by the agonists ATP and UTP, as demonstrated by single-cell Ca2+ responses

Desensitization of P2U receptor in neuronal cell line. Different control by the agonists ATP and UTP, as demonstrated by single-cell Ca2+ responses

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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