The TIPP opioid peptide family: Development of ? antagonists, ? agonists, and mixed ? agonist/? antagonists

Schiller, Peter W.; Weltrowska, Grazyna; Berezowska, Irena; Nguyen, Thi M.‐D.; Wilkes, Brian C.; Lemieux, Carole; Chung, Nga N.

doi:10.1002/(sici)1097-0282(1999)51:6<411::aid-bip4>3.0.co;2-z

Cited by 104 publications

(70 citation statements)

References 59 publications

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“…[ 35 S]GTP␥S, [ 3 H]adenosine, and coelanterazine were from PerkinElmer Life Sciences. SNC-80 was from Tocris Cookson, and TIPP and TICP were synthesized as previously described (15). G418, Dulbecco's modified Eagle's medium, fetal bovine serum, glutamine, penicillin, and streptomycin were purchased from Wisent.…”

Section: Methodsmentioning

confidence: 99%

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

Audet

Galès

Archer-Lahlou

et al. 2008

Journal of Biological Chemistry

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Heptahelical receptors communicate extracellular information to the cytosolic compartment by binding an extensive variety of ligands. They do so through conformational changes that propagate to intracellular signaling partners as the receptor switches from a resting to an active conformation. This active state has been classically considered unique and responsible for regulation of all signaling pathways controlled by a receptor. However, recent functional studies have challenged this notion and called for a paradigm where receptors would exist in more than one signaling conformation. This study used bioluminescence resonance energy transfer assays in combination with ligands of different functional profiles to provide in vivo physical evidence of conformational diversity of ␦-opioid receptors (DORs). DORs and ␣ i1 ␤ 1 ␥ 2 G protein subunits were tagged with Luc or green fluorescent protein to produce bioluminescence resonance energy transfer pairs that allowed monitoring DOR-G protein interactions from different vantage points. Results showed that DORs and heterotrimeric G proteins formed a constitutive complex that underwent structural reorganization upon ligand binding. Conformational rearrangements could not be explained by a two-state model, supporting the idea that DORs adopt ligand-specific conformations. In addition, conformational diversity encoded by the receptor was conveyed to the interaction among heterotrimeric subunits. The existence of multiple active receptor states has implications for the way we conceive specificity of signal transduction.Heptahelical receptors are versatile membrane proteins that play an important role in cellular communication. They do so by recognizing a large variety of extracellular ligands that convey information to the intracellular compartment by modifying receptor conformation upon binding. These structural modifications then trigger an array of biochemical changes that ultimately control vital processes within the cell. Traditionally, conformational changes induced by ligand binding have been thought to shift equilibrium between an active and an inactive conformation of the receptor. According to this classical view, all agonists would stabilize a single active state that equally effectively stimulates all signaling pathways controlled by the receptor (1). In consequence, ligand ability to stabilize this unique active state would be the only determinant of ligand efficacy at all functional readouts. Furthermore, this model predicts that ligand rank order of efficacy across different readouts should be maintained, representing a progressive accumulation (or decrease) of the single active state of the receptor (2).However, recent data have challenged this view, suggesting that the complexity of heptahelical receptor signaling cannot be based on the accumulation of a single active receptor conformation, and efficacy cannot be restricted to only a quantitative dimension (3, 4). Evidence supporting this assertion has been largely based on functional studies whose results ...

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Section: Methodsmentioning

confidence: 99%

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

Audet

Galès

Archer-Lahlou

et al. 2008

Journal of Biological Chemistry

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106

102

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“…Tic-deltorphin is a synthetic peptide with antagonistic properties and high ␦ opioid receptor selectivity (Schiller et al, 1999). When hDOR-C351I G i1 ␣ was coexpressed with hMOR, 100 nM Tic-deltorphin promoted no G␣ activation (98 Ϯ 4%) and was able to efficiently antagonize […”

Section: G␣ Subunit Activation By Nonfused Coexpressed Receptorsmentioning

confidence: 99%

μ-δ Opioid Receptor Functional Interaction: Insight Using Receptor-G Protein Fusions

Snook¹,

Milligan²,

Kieffer³

et al. 2006

J Pharmacol Exp Ther

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Fusion proteins between a receptor and a pertussis toxininsensitive G i ␣ subunit were used to gain insight into the molecular interactions that take place upon and ␦ opioid receptor heterodimerization. When opioid receptor-G i1 ␣ fusions were coexpressed with nonfused ␦ opioid receptors in human embryonic kidney 293 cells, or vice versa, receptor heterodimers were detected by coimmunoprecipitation. In pertussis toxin-treated cells, receptor coexpression decreased the amount of guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) incorporated in the fused G␣ protein after the addition of agonists specific for the receptor-G i1 ␣ fusion. In addition, activation of the G␣ protein occurred in heterodimers upon addition of an agonist specific for the nonfused receptor.It remained unaffected by an inverse agonist specific for the receptor-G i1 ␣ fusion. These data suggest that signaling through the receptor-G i1 ␣ fusion protein is impaired in heterodimers and support a mechanism in which activation of the G␣ subunit is promoted by a direct interaction with the nonfused receptor. Alternatively, receptor coexpression did not modify the ligand binding properties for the high-affinity state of the receptor-G i1 ␣ fusion nor the EC 50 values for agonist-induced [35 S]GTP␥S incorporation in the G i1 ␣ subunit. In addition, no binding competition was observed between ␦ and ligands. Together, the data point to -␦ opioid receptor heterodimers formed by contact interactions between monomers that retain their structural integrity.Genes coding for ␦, , and opioid receptor types have been identified and isolated from different vertebrates and belong to the G protein-coupled receptor (GPCR) superfamily. The opioid receptors and endogenous opioid peptides form a neuromodulatory system that plays a major role in the control of nociceptive pathways. The opioid system also modulates affective behavior, neuroendocrine physiology, and controls autonomic functions such as respiration, blood pressure, thermoregulation, and gastrointestinal motility. Importantly, the receptors are targets for exogenous narcotic opiate alkaloids that constitute a major class of drugs of abuse (Massotte and Kieffer, 1998;Bodnar and Hadjimarkou, 2003).GPCR signaling is a complex process whose modulation likely proceeds from many intricate factors. Recently, a possible involvement of the receptor oligomerization state has received growing attention since existence of homo-and heterodimers has been postulated for an increasing number of GPCRs (for reviews, see Milligan, 2004;Park et al., 2004;Prinster et al., 2005). Arguments in favor of a spatial proximity between receptor molecules mainly arose from coimmunoprecipitation studies and more recently from bioluminescence and fluorescence resonance energy transfer experiments (for review, see Milligan and Bouvier, 2005). However, establishing physical proximity between receptors does not necessarily imply functional interactions between them. Even when modifications of the signaling properties seemed ...

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“…TIPP and some of its analogues 2 have become widely used pharmacological tools. A molecular mechanics study (grid search and energy minimization) performed with TIP and TIPP resulted in low-energy structures showing various patterns of aromatic ring stacking.…”

Section: Introductionmentioning

confidence: 99%

[Aladan³]TIPP: A fluorescent δ‐opioid antagonist with high δ‐receptor binding affinity and δ selectivity

et al. 2004

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The TIPP opioid peptide family: Development of ? antagonists, ? agonists, and mixed ? agonist/? antagonists

Cited by 104 publications

References 59 publications

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

μ-δ Opioid Receptor Functional Interaction: Insight Using Receptor-G Protein Fusions

[Aladan³]TIPP: A fluorescent δ‐opioid antagonist with high δ‐receptor binding affinity and δ selectivity

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The TIPP opioid peptide family: Development of ? antagonists, ? agonists, and mixed ? agonist/? antagonists

Cited by 104 publications

References 59 publications

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

Bioluminescence Resonance Energy Transfer Assays Reveal Ligand-specific Conformational Changes within Preformed Signaling Complexes Containing δ-Opioid Receptors and Heterotrimeric G Proteins

μ-δ Opioid Receptor Functional Interaction: Insight Using Receptor-G Protein Fusions

[Aladan3]TIPP: A fluorescent δ‐opioid antagonist with high δ‐receptor binding affinity and δ selectivity

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[Aladan³]TIPP: A fluorescent δ‐opioid antagonist with high δ‐receptor binding affinity and δ selectivity