Altered adenylyl cyclase responsiveness subsequent to point mutations of Asp 128 in the third transmembrane domain of the δ-opioid receptor

A, Cavalli; Babey, A. M.; Loh, Horace H.

doi:10.1016/s0306-4522(99)00280-8

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…75G0 . 07 nM (Cavalli et al 1999) (Pepin et al 1997)) does not bind to ZFOR4, and with very low affinity to ZFOR1 (K i Z953 nM; Rodriguez et al 2000). The fact that the d-opioid receptor of the newt presents a K i Z 499 nM for DPDPE (Bradford et al 2006), which is an intermediate value between those established for the mammalian and zebrafish d receptors, indicates that the DPDPE selectivity is gradually lost when moving down in the evolutionary scale and suggests that this ligand may not be suitable for determining the d-binding profile in such organisms.…”

Section: Expression Studiesmentioning

confidence: 99%

Characterization of a new duplicate δ-opioid receptor from zebrafish

Pinal¹,

Martin²,

González-Núñez³

et al. 2006

Journal of Molecular Endocrinology

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A new full-length cDNA (ZFOR4) that encodes an opioid receptor has been isolated from the teleost zebrafish. The encoded polypeptide is 375 amino acids long and shows high sequence similarity to other d-opioid receptors, including ZFOR1, the other d-opioid receptor from zebrafish previously characterized by us. In situ hybridization studies have revealed that ZFOR4 mRNA is highly expressed in particular brain areas that coincide with the expression of the d-opioid receptor in other species. Pharmacological analysis of ZFOR4 shows specific and saturable binding with [

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Section: Expression Studiesmentioning

confidence: 99%

Characterization of a new duplicate δ-opioid receptor from zebrafish

Pinal¹,

Martin²,

González-Núñez³

et al. 2006

Journal of Molecular Endocrinology

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“…Truncation of the carboxyl tail of the -opioid receptor abolished the ability of DAMGO but not morphine ability to inhibit the adenylyl cyclase activity (Surratt et al, 1994). Similar truncation of the carboxyl tail of the ␦-opioid receptor resulted in the attenuation of [D-Pen 2 ,DPen 5 ]-enkephalin-mediated activation of the phospholipase C ␤ (Hirst et al, 1998 within the third TM domain or the Tyr 308 within the seventh TM domain resulted in the constitutive activation of the ␦-opioid receptor (Befort et al, 1999;Cavalli et al, 1999). Because these residues could contribute to an intramolecular interaction that stabilizes the ␦-opioid receptor in its inactive form, these mutations would allow the movement within the third TM domain and suggested the involvement of second intracellular loop of the opioid receptor in the G protein activation.…”

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confidence: 99%

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Chaipatikul

Loh²,

Law³

2003

J Pharmacol Exp Ther

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The mechanism for the differential regulation of the -opioid receptor by agonists is investigated by identifying the receptor domains used to define the relative efficacies of three -opioid with Ala reduced the potency of DAMGO but not that of morphine PL017. Meanwhile, mutation of Thr 279 to Ala increased the potencies of morphine and PL017 but not that of DAMGO. The I278A mutation decreased the DAMGO coupling efficiency but increased the PL017 coupling efficiency. The R280A mutation resulted in the increase in PL017 potency and coupling efficiency without altering those of DAMGO and morphine. Thus, these mutation studies suggested that the activation of -opioid receptor and interaction between the critical domains such as RRITR within third intracellular loop and the G proteins are agonist-selective.Opioid receptors are members of the G protein-coupled receptors (GPCRs) (Wess, 1998). Mutational analyses of many members of GPCR family provide evidence that the second and third intracellular loops and the C-terminal tails are involved in the receptor/G protein coupling (for review, see Helmreich and Hofmann, 1996). However, the consensus sequence in the receptor/G protein coupling has yet to be identified. Possibly, in addition to its primary sequence, a secondary structure of the receptor, i.e., the amphipatic ␣-helix is a determinant for G proteins and receptor interaction. Sequence alignment revealed that BBXXB (B stands for basic amino acids and X is any amino acid) sequence was commonly found in the regions of GPCRs critical for G protein interaction. Detailed studies further suggested that the basic amino acids in BBXXB motif are crucial for activating Gprotein. In the human platelet-activating factor (PAF) receptor, mutation in the BBXXB motif resulted in mutants with low-affinity binding for PAF and less effective in mediating phosphatidylinositol hydrolysis (Parent et al., 1996). Use of peptides corresponding to the third intracellular loop of the ␦-opioid receptor, Georgoussi et al. (1997) and Merkouris et al. (1996) demonstrated the importance of this motif in the opioid receptor/G protein interaction. The basic amino acids within this motif have been suggested to form a polar pocket interacting with motifs in other domains of the GPCR, such as the conserved (D/E)RY motif at the N terminus of the second intracellular loop, thus stabilizing the receptor in the inactive states. Binding of the agonist results in transmembrane (TM) movement, thus disrupting such interaction and resulted in the receptor activation. This hypothesis is supported by studies with the mutation of amino acids within this region and the Ala insertion studies that resulted in constitutive activities of the muscarinic receptor (Liu et al

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“…One study demonstrated that the replacement of the Asp residue in TM3 with Ala, His, or Lys would endow the mutated receptors with constitutive activity. Whereas naltrindole was still an antagonist at the Asp to Ala mutant, it became an agonist at the receptor with the Ala to Lys mutation (18). Another study mutated the same Asp residue in TM3, the Tyr residue immediately below Asp in TM3, and a Tyr residue in TM7.…”

mentioning

confidence: 99%

Switching Agonist/Antagonist Properties of Opiate Alkaloids at the δ Opioid Receptor Using Mutations Based on the Structure of the Orphanin FQ Receptor

Meng

Wei

Hoversten

et al. 2000

Journal of Biological Chemistry

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In an earlier study, we have demonstrated that by mutating five amino acid residues to those conserved in the opioid receptors, the OFQ receptor could be converted to a functional receptor that bound many opioid alkaloids with nanomolar affinities. Surprisingly, when the reciprocal mutations, Lys-214 3 Ala (TM5), Ile-277 3 Val/His-278 3 Gln/Ile-279 3 Val (TM6), and Ile-304 3 Thr (TM7), are introduced in the ␦ receptor, neither the individual mutations nor their various combinations significantly reduce the binding affinities of opioid alkaloids tested. However, these mutations cause profound alterations in the functional characteristics of the mutant receptors as measured in guanosine 5-3-O-(thio)triphosphate binding assays. Some agonists become antagonists at some constructs as they lose their ability to activate them. Some alkaloid antagonists are transformed into agonists at other constructs, but their agonistic effects can still be blocked by the peptide antagonist TIPP. Even the ␦ inverse agonist 7-benzylidenenaltrexone becomes an agonist at the mutant containing both the Ile-277 3 Val/His-278 3 Gln/Ile-279 3 Val and Ile-304 3 Thr mutations. Thus, although the mutated residues are thought to be part of the binding pocket, they are critically involved in the control of the ␦ receptor activation process. These findings shed light on some of the structural bases of ligand efficacy. They are also compatible with the hypothesis that a ligand may achieve high affinity binding in several different ways, each having different effects on receptor activation.

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Altered adenylyl cyclase responsiveness subsequent to point mutations of Asp 128 in the third transmembrane domain of the δ-opioid receptor

Cited by 15 publications

References 25 publications

Characterization of a new duplicate δ-opioid receptor from zebrafish

Characterization of a new duplicate δ-opioid receptor from zebrafish

Ligand-Selective Activation of μ-Opioid Receptor: Demonstrated with Deletion and Single Amino Acid Mutations of Third Intracellular Loop Domain

Switching Agonist/Antagonist Properties of Opiate Alkaloids at the δ Opioid Receptor Using Mutations Based on the Structure of the Orphanin FQ Receptor

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