Go mediates the coupling of the mu opioid receptor to adenylyl cyclase in cloned neural cells and brain.

Carter, Bruce D.; Medzihradsky, Fedor

doi:10.1073/pnas.90.9.4062

Cited by 104 publications

(44 citation statements)

References 42 publications

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“…Some receptors, such as rhodopsin, do not distinguish between G i family members. Other G i coupled receptors are able to distinguish to different degrees among G i family members (25,(43)(44)(45)(46)(47). The 5-HT 1B receptor is an example of such selectivity as this receptor fails to couple with transducin or Chi6, the transducin-like chimera.…”

Section: -Ht 1b Receptor Binding Sites On Inhibitory G Proteinmentioning

confidence: 99%

Molecular Determinants of Selectivity in 5-Hydroxytryptamine1B Receptor-G Protein Interactions

Bae¹,

Anderson²,

Flood³

et al. 1997

Journal of Biological Chemistry

289

199

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The recognition between G protein and cognate receptor plays a key role in specific cellular responses to environmental stimuli. Here we explore specificity in receptor-G protein coupling by taking advantage of the ability of the 5-hydroxytryptamine 1B (5-HT 1B ) receptor to discriminate between G protein heterotrimers containing G␣ i1 or G␣ t . G i1 can interact with the 5-HT 1B receptor and stabilize a high affinity agonist binding state of this receptor, but G t cannot. A series of G␣ t /G␣ i1 chimeric proteins have been generated in Escherichia coli, and their functional integrity has been reported previously (Skiba, N. P., Bae, H., and Hamm, H. E. (1996) J. Biol. Chem. 271, 413-424). We have tested the functional coupling abilities of the G␣ t /G␣ i1 chimeras to 5-HT 1B receptors using high affinity agonist binding and receptor-stimulated guanosine 5-3-O-(thio)triphosphate (GTP␥S) binding. In the presence of ␤␥ subunits, amino acid residues 299 -318 of G␣ i1 increase agonist binding to the 5-HT 1B receptor and receptor stimulation of GTP␥S binding. Moreover, G␣ i1 containing only G␣ t amino acid sequences from this region does not show any coupling ability to 5-HT 1B receptors. Our studies suggest that the ␣4 helix and ␣4-␤6 loop region of G␣s are an important region for specific recognition between receptors and G i family members.The heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) mediate signaling from a large number of diverse heptahelical cell surface receptors to a variety of intracellular effectors. These pathways control numerous essential functions in all tissues and are ubiquitous throughout eukaryotes (1-3). A large body of work investigating the mechanisms underlying receptor-G protein interactions now exists. The early view that signaling selectivity would manifest itself on the basis of specific protein interactions allowing a receptor to couple with a unique G protein to modulate a single effector is no longer tenable with the accumulating evidence of a network of interactions that converge and diverge at multiple levels. Even in the earliest receptor-G protein reconstitution studies using phospholipid vesicles, it was clear that, while there were large differences in the efficiencies of coupling among the major families of G proteins, receptors were capable of activating multiple G proteins from distinct families (4, 5).Elucidation of the crystal structures of ␣ subunits in both active (6, 7) and inactive conformations (8), an isolated ␤␥ subunit (9) and the ␣␤␥ heterotrimer (10, 11), has begun to define a mechanistic basis for data from mutagenesis, chimera, and peptide studies defining functional domains on G protein subunits (12)(13)(14)(15)(16)(17). A variety of studies have implicated the C terminus of ␣ subunits in mediating receptor-G protein selectivity (13-15). Synthetic peptides from the C terminus of ␣ t (amino acids 340 -350) have been shown to stabilize the active conformation of metarhodopsin II (17) while alanine scanning mutagenesis of the same regi...

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Section: -Ht 1b Receptor Binding Sites On Inhibitory G Proteinmentioning

confidence: 99%

Molecular Determinants of Selectivity in 5-Hydroxytryptamine1B Receptor-G Protein Interactions

Bae¹,

Anderson²,

Flood³

et al. 1997

Journal of Biological Chemistry

289

199

View full text Add to dashboard Cite

show abstract

“…On the other hand, the MOR-selective agonist ,N-MePhe 4 ,Gly-ol 5 ]enkephalin (DAMGO) was found to activate Ga o to a greater extent than either Ga i2 or Ga i3 (Clark et al, 2008). Furthermore, in cultured neurons or neuronal-like cells, MOR has been shown to couple to AC (Carter and Medzihradsky, 1993) and N-type Ca 2 + channels (Hescheler et al, 1987;Moises et al, 1994) primarily via activation of Ga o . Despite the abundance of Ga o in the brain and evidence from in vitro studies that Ga o modulates signaling downstream of MOR, together with a recent report that Ga o may be involved in opioid dependence (Kest et al, 2009), findings in vivo have primarily implicated Ga i2 and/or Ga z proteins as mediators of opioid agonist antinociception (Raffa et al, 1994;Sanchez-Blazquez et al, 1995Standifer et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Mu-Opioid Receptor Coupling to Gαo Plays an Important Role in Opioid Antinociception

Lamberts

Jutkiewicz

Mortensen

et al. 2011

Neuropsychopharmacol

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Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Ga i/o -type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Ga i/o isoform, Ga o . However, studies in vivo evaluating morphine-mediated antinociception have not supported these findings. The aim of the present work was to evaluate the contribution of Ga o to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a Ga o null transgenic mouse strain. Male wild-type and Ga o heterozygous null (Ga o + /À) mice were tested for opioid antinociception in the hot plate test or the warm-water tail withdrawal test as measures of supraspinal or spinal antinociception, respectively. Reduction in Ga o levels attenuated the supraspinal antinociception produced by morphine, methadone, and nalbuphine, with the magnitude of suppression dependent on agonist efficacy. This was explained by a reduction in both high-affinity MOR expression and MOR agoniststimulated G protein activation in whole brain homogenates from Ga o + /À and Ga o homozygous null (Ga o À/À) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Ga o + /À and wild-type mice and high-affinity MOR expression was unchanged in spinal cord tissue. However, the action of the partial agonist nalbuphine was compromised, showing that reduction in Ga o protein does decrease spinal antinociception, but suggesting a higher Ga o protein reserve. These results provide the first in vivo evidence that Ga o contributes to maximally efficient MOR signaling and antinociception.

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“…It seems also obvious that the same Gα subunit can regulate different effectors [13,42] and conversely that the same effector (i.e. adenylate cyclase) can be regulated by different Gα subunits [13,38]. It was suggested that these differences observed in the different cellular models were related only to the opioid receptors and the Gα expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the blockade of one of the α-subunits that mediates etorphine action on adenylate cyclase would not be sufficient for the observation of any significant decrease on the maximal inhibition level, because the other δ-opioid-receptor-activated Gα protein(s) could ensure the coupling between opioid receptors and adenylate cyclase. In the neuroblastoma cell line SH-SY 5Y, the three antisera directed against G i α1, G i α2, G i α3 and G o α impair the coupling of δ-opioid receptors to adenylate cyclase, demonstrating that the mediation of the inhibition of adenylate cyclase involves several Gα subunits [38]. We showed previously that a sustained stimulation of δ-opioid receptors by etorphine led to a different heterologous desensitization between opioid, D # -dopaminergic and α # -adrenergic receptors [39].…”

Section: Discussionmentioning

confidence: 99%

Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE

Allouche

Polastron

Hasbi

et al. 1999

Biochemical Journal

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Differences in the specificity of coupling of δ-opioid receptor with G-protein have been reported in the literature. We have observed a differential desensitization of δ-opioid receptors, endogenously expressed in the neuroblastoma cell line SK-N-BE, induced by peptide and alkaloid agonists. By combining photoaffinity labelling of receptor-activated G-proteins with [α-32P]azidoanilide-GTP and an anti-sense oligodeoxynucleotide strategy, we examined whether the chemical nature of opioid agonists, alkaloid or peptide, has a critical role in determining a Giα/Goα-protein-selective activation by the human δ-opioid receptors. Etorphine, a non-selective alkaloid agonist, was shown to stimulate the incorporation of [α-32P]azidoanilide-GTP into Giα1, Giα2, Giα3 and pertussis-toxin-insensitive Gα subunits. In contrast, [D-Pen2,D-Pen5]enkephalin (DPDPE; Pen is penicillamine) and Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I), selective peptide agonists, mainly activated Giα2 and Goα2 subunits. The ‘knock-down’ of Goα2 subunits by anti-sense oligodeoxynucleotides selectively decreased the inhibition of adenylate cyclase induced by DPDPE and deltorphin I, whereas anti-sense oligodeoxynucleotides directed against Giα2 subunits only decreased the potency of etorphine in inhibiting cAMP accumulation. These results suggest that the nature of the agonist, peptide or alkaloid is critical in determining the interaction between human δ-opioid receptors and Gα subunits.

show abstract

Go mediates the coupling of the mu opioid receptor to adenylyl cyclase in cloned neural cells and brain.

Cited by 104 publications

References 42 publications

Molecular Determinants of Selectivity in 5-Hydroxytryptamine1B Receptor-G Protein Interactions

Molecular Determinants of Selectivity in 5-Hydroxytryptamine1B Receptor-G Protein Interactions

Mu-Opioid Receptor Coupling to Gαo Plays an Important Role in Opioid Antinociception

Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE

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