Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X

Pan, Ying Xian; Xu, Jin; Mahurter, Loriann; Xu, Mingming; Gilbert, Annie Kim; Pasternak, Gavril W.

doi:10.1016/s0006-291x(03)00089-5

Cited by 90 publications

(81 citation statements)

References 21 publications

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“…The importance of brain region-dependent variable -opioid receptor expression (30,31) and function (25,32) for the functional consequences of the 118AϾG variant might be a major reason for the failed or contradictory results of previous investigations in cell cultures (10 -14) that contrast with the consistent clinical findings of decreased opioid effects in carriers of variant 118G (1-9). To which extent region-specific expression of -opioid receptor splice variants (33,34) and coupling to G ␣ and G ␤ ␥ subunits (35,36), which are known to influence the -opioid receptor signaling, contribute to the brain region-dependent effects of the N40D variant, may be addressed in the future.…”

Section: Discussionmentioning

confidence: 99%

A Common Human μ-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain

Oertel

Kettner

Scholich

et al. 2009

Journal of Biological Chemistry

140

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The single nucleotide polymorphism 118A>G of the human -opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the -opioid receptor-specific agonist DAMGO, we analyzed the -opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (S II ) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D -opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the S II region of homo-and heterozygous carriers of the variant 118G allele (n ‫؍‬ 18), DAMGO was only 62% as efficient (p ‫؍‬ 0.002) as in homozygous carriers of the wild-type 118A allele (n ‫؍‬ 15). In contrast, the number of [ 3 H]DAMGO binding sites was unaffected. Hence, the -opioid receptor G-protein coupling efficacy in S II of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p < 0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of -opioid receptor variant N40D.The human -opioid receptor variant N40D coded by the single nucleotide polymorphism (SNP) 2 118AϾG of the -opioid receptor gene, OPRM1 (dbSNP rs1799971; allelic frequency 8.2-17%) has been found to be associated with diminished opioid effects in experimental (1-5) and clinical (6 -9) settings. However, in vitro experiments trying to elucidate the underlying molecular mechanisms provided inconsistent results, falling short to support the comparatively strong clinical evidence of decreased opioid effects in carriers of the variant 118G allele.Among the reported molecular consequences of the 118AϾG polymorphism is a three times higher binding affinity of ␤-endorphin at the N40D -opioid receptors expressed in transfected Syrian hamster adenovirus-12-induced tumor cells (AV-12), whereas the affinity of other exogenous opioids was unaffected (10). In contrast, a leftward shift of the potencies of DAMGO and morphine-mediated Ca 2ϩ channel inhibition has been shown in N40D variant -opioid receptor expressed in rat sympathetic superior cervical ganglion (SCG) neurons (11). However, both findings of a higher ligand affinity and potency were not reproduced in three attempts using N40D variant -opioid receptors transfected Cercopithecus aethiops kidney cells (COS), human 293 embryonic kidney cells (HEK293), and again AV-12 cells (12-14). Moreover, they do not explain the decreased clinical opioid potency. As an alternative mechanism, decreased -opioid receptor expression caused...

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Section: Discussionmentioning

confidence: 99%

A Common Human μ-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain

Oertel

Kettner

Scholich

et al. 2009

Journal of Biological Chemistry

140

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“…The truncations had little effect on ED 50 values, but significantly reduced DAMGO-and morphine-induced maxi- ]DAMGO), a mu agonist, with high affinity and with only subtle differences in selectivity for the endogenous opioid peptides dynorphin A and β endorphin (18,25,26). However, in [ 35 S]GTPγS-binding assays, these C-terminal splice variants displayed marked differences in mu opioid-induced G protein coupling in both potency (EC 50 ) and efficacy (% of maximal stimulation) (26,27), suggesting that the distal carboxyl terminal sequences influence mu agonist-induced receptor-G protein coupling and signal transduction.…”

Section: S]mentioning

confidence: 96%

“…Increasing evidence implies that the full-length 7TM C-terminal splice variants are pharmacologically important. At the mRNA level, they show region-specific expressions in rodents and humans (18)(19)(20), and long-term morphine treatment selectively increases C-terminal variant mRNA expression in various brain regions by as much as 300-fold (21). At the protein level, different C-terminal epitopes also differ in their cellular (i.e., pre-vs. postsynaptic) and regional distributions (22,23).…”

Section: Introductionmentioning

confidence: 99%

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Xu¹,

Lu²,

Narayan³

et al. 2017

Journal of Clinical Investigation

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“…This inability to reconcile the diverse pharmacology of -opioids with their binding selectivity led to the proposal of multiple -opioid-receptors (7), a concept initially proposed based on binding and pharmacological studies in animal models and subsequently confirmed with the identification of a large number of splice variants of the cloned -opioid-receptor MOR-1 in mice, rats, and humans ( Fig. 1A) (8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

Pan

et al. 2009

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

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100

140

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Heroin remains a major drug of abuse and is preferred by addicts over morphine. Like morphine, heroin has high affinity and selectivity for -receptors, but its residual analgesia in exon 1 MOR-1 knockout mice that do not respond to morphine suggests a different mechanism of action. MOR-1 splice variants lacking exon 1 have been observed in mice, humans, and rats, raising the possibility that they might be responsible for the residual heroin and morphine-6␤-glucuronide (M6G) analgesia in the exon 1 knockout mice. To test this possibility, we disrupted exon 11 of MOR-1, which eliminates all of the variants that do not contain exon 1. Morphine and methadone analgesia in the exon 11 knockout mouse was normal, but the analgesic actions of heroin, M6G, and fentanyl were markedly diminished in the radiant heat tailflick and hot-plate assays. Similarly, the ability of M6G to inhibit gastrointestinal transit was greatly diminished in these exon 11 knockout mice, whereas the ability of morphine was unchanged. These findings identify receptors selectively involved with heroin and M6G actions and confirm the relevance of the exon 11-associated variants and raise important issues regarding the importance of atypical truncated G-protein-coupled receptors.knockout ͉ analgesia ͉ opiate receptor

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Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X

Cited by 90 publications

References 21 publications

A Common Human μ-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain

A Common Human μ-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

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