Polar Residues in the Transmembrane Domains of the Type 1 Angiotensin II Receptor Are Required for Binding and Coupling

Monnot, Catherine; Bihoreau, Claire; Conchon, Sophie; Curnow, Kathleen M.; Corvol, Pierre; Clauser, Éric

doi:10.1074/jbc.271.3.1507

Cited by 203 publications

(153 citation statements)

References 33 publications

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“…For example, co-expression of truncated ␤ 2 ARs that individually do not transmit a signal resulted in formation of functional receptors (14). Similarly, co-expression of two different binding-defective point mutants of the angiotensin receptors restored binding activity (15). The existence of GPCR dimers is also shown by the use of two chimeric receptor molecules in which the C-terminal receptor domains were exchanged between the ␣ 2c -adrenergic receptor and the m3-muscarinic receptor; transfection of either of these receptors did not result in any detectable binding sites, whereas their co-expression resulted in the generation of a significant number of specific binding sites (16).…”

Section: Discussionmentioning

confidence: 99%

Dimerization of the δ Opioid Receptor:

Cvejic

Devi

1997

Journal of Biological Chemistry

429

138

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Dimerization of G-protein-coupled receptors has been increasingly noted in the regulation of their biological activity. However, its involvement in agonist-induced receptor internalization is not well understood. In this study, we examined the ability of mouse ␦-opioid receptors to dimerize and the role of receptor dimerization in agonist-induced internalization. Using differentially (Flag and c-Myc) epitope-tagged receptors we show that ␦-opioid receptors exist as dimers. The level of dimerization is agonist dependent. Increasing concentrations of agonists reduce the levels of dimer with a corresponding increase in the levels of monomer. Interestingly, morphine does not affect the levels of either form. It has been shown that morphine, unlike other opioid agonists, does not induce receptor internalization. This suggests a relationship between the ability of agonists to reduce the levels of dimer and to induce receptor internalization. The time course of the agonist-induced decrease of ␦-opioid receptor dimers is shorter than the time course of internalization, suggesting that monomerization precedes the agonist-induced internalization of the receptor. Furthermore, we found that a mutant ␦-opioid receptor, with a 15-residue C-terminal deletion, does not exhibit dimerization. This mutant receptor has been shown to lack the ability to undergo agonist-induced internalization. These results suggest that the interconversion between the dimeric and monomeric forms plays a role in opioid receptor internalization.The opioid receptor family, a member of the superfamily of G-protein-coupled receptors (GPCRs), 1 consists of three receptor types: ␦, , and . The opioid receptors transmit the signals induced by binding of opioid peptides and opiate alkaloids, such as morphine. Continuous or repeated exposure to opioid ligands causes decreased sensitivity to the drug and reduced cellular response; this response is regulated by multiple mechanisms. Long-term exposure to opioid ligands causes receptor down-regulation as a result of the receptor degradation (1-4).Short-term treatment with opioid ligands causes rapid loss of receptors from the surface of the cell as a result of the receptor endocytosis (5-7). Both of these effects require the intact Cterminal tail of the receptor (4, 7). Although deletion of the C-terminal tail substantially reduces the extent of both downregulation and rapid internalization, point mutations within this region reduce the extent of internalization without affecting down-regulation, suggesting that these two responses are differentially regulated (7). Different opioid ligands induce different effects on rapid internalization of the opioid receptors. Morphine, unlike most of the opioid agonists, does not induce rapid internalization of the opioid receptors (5, 8). An exact mechanism of the opioid receptor internalization is not known, although it has been suggested that the rapid endocytosis of the receptors is mediated through the classic endocytic pathway (5, 7). Possible events that would precede ...

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Section: Discussionmentioning

confidence: 99%

Dimerization of the δ Opioid Receptor:

Cvejic

Devi

1997

Journal of Biological Chemistry

429

138

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“…For example, co-expression of different point mutant forms of the angiotensin II receptor can restore ligand binding activity but not signaling (51), indicating that complete trans complementation does not occur. Whether restoration of ligand binding occurs by transmembrane domain swapping between receptors (52), or by one mutant receptor providing the "address" site for agonist binding and the other the "message" site (53) is not clear.…”

Section: Discussionmentioning

confidence: 99%

Subunits of a Yeast Oligomeric G Protein-coupled Receptor Are Activated Independently by Agonist but Function in Concert to Activate G Protein Heterotrimers

Chinault

Overton²,

Blumer³

2004

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) form dimeric or oligomeric complexes in vivo. However, the function of oligomerization in receptor-mediated G protein activation is unclear. Previous studies of the yeast ␣-factor receptor (STE2 gene product) have indicated that oligomerization promotes signaling. Here we have addressed the mechanism by which oligomerization facilitates G protein signaling by examining the ability of ligand binding-and G protein coupling-defective ␣-factor receptors to form complexes in vivo and to correct their signaling defects when co-expressed (trans complementation). Newly and previously identified receptor mutants indicated that ligand binding involves the exofacial end of transmembrane domain (TM) 4, whereas G protein coupling involves ic1, ic3, the C-terminal tail, and the intracellular ends of TM2 and TM3. Mutant receptors bearing substitutions in these domains formed homo-oligomeric or hetero-oligomeric complexes in vivo, as indicated by results of fluorescence resonance energy transfer experiments. Co-expression of ligand binding-and G protein coupling-defective mutant receptors did not significantly improve signaling. In contrast, co-expression of ic1 and ic3 mutations in trans but not in cis significantly increased signaling efficiency. Therefore, we suggest that subunits of the ␣-factor receptor: 1) are activated independently rather than cooperatively by agonist, and 2) function in a concerted fashion to promote G protein activation, possibly by contacting different subunits or regions of the G protein heterotrimer.

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“…B a s e d o n a n u m b e r o f pharmacological, mutagenesis and computer-oriented modeling studies [63][64][65][66][67][68][69][70][71][72][73][74][75][76], the general agreement is that a positively-charged residue of Lys199 on transmembrane domain (TM)-5 of the AT1 receptor interacts with the -carboxyl group of Phe8 in Ang II. This interaction is crucial for high affinity binding of Ang II to the receptor.…”

Section: Functional Domains Of the At1 Receptormentioning

confidence: 99%

The angiotensin II type 1 receptor and receptor-associated proteins

et al. 2001

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The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

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Polar Residues in the Transmembrane Domains of the Type 1 Angiotensin II Receptor Are Required for Binding and Coupling

Cited by 203 publications

References 33 publications

Dimerization of the δ Opioid Receptor:

Dimerization of the δ Opioid Receptor:

Subunits of a Yeast Oligomeric G Protein-coupled Receptor Are Activated Independently by Agonist but Function in Concert to Activate G Protein Heterotrimers

The angiotensin II type 1 receptor and receptor-associated proteins

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