Differential blockade of morphine and morphine-6β-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein α subunits in rats

Rossi, Grace C.; Standifer, Kelly M.; Pasternak, Gavril W.

doi:10.1016/0304-3940(95)11977-5

Cited by 90 publications

(58 citation statements)

References 24 publications

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“…Antisense mapping of MOR-1 in both mice (Rossi et al, 1995a and rats (Rossi et al, 1994a(Rossi et al, , 1995b reveals very interesting findings (Table 16). Supraspinally, targeting exons 1 and 4 lowers morphine analgesia without impacting the effectiveness of morphine-6b-glucuronide (M6G).…”

Section: Characterization Of Mor-1 Splice Variantsmentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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Section: Characterization Of Mor-1 Splice Variantsmentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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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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“…The presence of these alternatively spliced isoforms raises the possibility that they may mediate pharmacologically distinct actions. The limited selectivity of traditional NOS inhibitors precludes their use in exploring this question, but antisense paradigms provide an extraordinary selectivity (34)(35)(36)(37) and the ability to evaluate the functional activity of splice variants through the selective targeting of individual exons (37)(38)(39)(40)(41)(42). In the current study, we have utilized an antisense approach to define the NOS isoforms involved with morphine analgesia and tolerance.…”

mentioning

confidence: 99%

Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: Evidence for opposing NO actions on morphine analgesia and tolerance

Kolesnikov

Pan

Babey

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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106

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Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Downregulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with N G -nitro-L-arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down-regulate splice variants opens many areas in the study of nNOS and other proteins.

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Differential blockade of morphine and morphine-6β-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein α subunits in rats

Cited by 90 publications

References 24 publications

Mu Opioids and Their Receptors: Evolution of a Concept

Mu Opioids and Their Receptors: Evolution of a Concept

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

Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: Evidence for opposing NO actions on morphine analgesia and tolerance

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