Evidence for the dual coupling of the rat neurotensin receptor with pertussis toxin‐sensitive and insensitive G‐proteins

Gailly, Philippe; Najimi, Mustapha; Hermans, Emmanuel

doi:10.1016/s0014-5793(00)02095-0

Cited by 28 publications

(38 citation statements)

References 43 publications

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“…suggesting that this parameter mainly reflected nucleotide exchange at G i/o [20,53]. This result was confirmed by experiments with fusion proteins consisting of various G subunits covalently linked to rat NTS1 C-terminus [23].…”

Section: One Receptor One G Protein: Two Distinct Ways Of Influencinsupporting

confidence: 54%

“…An involvement of these G proteins in the functional correlates of NTS1 receptor stimulation was also suggested by experiments showing that intracellular injection of an antibody against the common C-terminus of G q and G 11 inhibited the NT-induced alterations in function of ion channels [77]. However, NT was also found to induce inhibition of adenylyl cyclase and stimulation of arachidonic acid production through interaction with G i/o -type G proteins in selected systems, such as CHO cells transfected with rat or human NTS1 [20,53,56] and rat neuroblastoma N1E115 cell line [11]. Furthermore, this peptide stimulated adenylyl cyclase through interaction with G s in cells transfected with rat or human NTS1 [62,69,79] and in human pancreatic cancer cells endogenously expressing the receptor [31], but not in human colonic adenocarcinoma HT29 cells [1].…”

Section: One Pluripotent Receptor Several Cells: How To Combine Econmentioning

confidence: 89%

“…The affinity of radiolabeled NT for wild-type NTS1 was decreased three-to fourfold in the presence of the stable GTP analog, GppNHp. Both NT affinity and GppNHp effect were strongly reduced after treatment of cell membranes with pertussis toxin, suggesting that the main G protein enhancing NT affinity was G i/o [20]. Furthermore, binding of radiolabeled NT to C-terminal truncated NTS1 expressed in CHO cells was totally insensitive to GppNHp, although this mutant receptor was still functionally coupled to G q/11 activation [28].…”

Section: One Receptor One G Protein: Two Distinct Ways Of Influencinmentioning

confidence: 99%

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Interactions between neurotensin receptors and G proteins

Pélaprat

2006

Peptides

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Abstract:Three neurotensin (NT) receptors have been cloned to date, two of which, NTS1 and NTS2, belonging to the family of seven transmembrane domain receptors coupled to G proteins (GPCRs). NTS1 and NTS2 may activate multiple signal transduction pathways, involving several G proteins. However, whereas NT acts as an agonist towards all NTS1-mediated pathways, this peptide exerts agonist or antagonist activities depending on the considered NTS2-mediated pathway. Studies on these receptors reinforce the concept of independence between multiple signals potentially mediated through a single GPCR, generating a wide diversity of functional responses depending on the host cell and the ligand.

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Section: One Receptor One G Protein: Two Distinct Ways Of Influencinsupporting

confidence: 54%

Section: One Pluripotent Receptor Several Cells: How To Combine Econmentioning

confidence: 89%

Section: One Receptor One G Protein: Two Distinct Ways Of Influencinmentioning

confidence: 99%

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Interactions between neurotensin receptors and G proteins

Pélaprat

2006

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“…However, stimulation of this receptor also activated other pathways such as production of arachidonic acid or cAMP, through G i/o or G s , respectively (Yamada et al, 1993;Gailly et al, 2000). Although coupling to G q/11 was previously reported to involve the third intracellular loop of NTS1 receptor (Yamada et al, 1994), we recently demonstrated that coupling to G i/o involved the carboxy-terminal portion of this receptor (Najimi et al, 2002).…”

mentioning

confidence: 55%

Differential Involvement of Intracellular Domains of the Rat NTS1 Neurotensin Receptor in Coupling to G Proteins: A Molecular Basis for Agonist-Directed Trafficking of Receptor Stimulus

Skrzydelski

Lhiaubet²,

Lebeau³

et al. 2003

Mol Pharmacol

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In this work, we evidenced characteristic features of agonistinduced trafficking of receptor stimulus for the rat neurotensin receptor 1 (NTS1). Thus, reverse potency orders between two agonists, EISAI-1 and neuromedin N, were observed in inositol 1,4,5-trisphosphate and cAMP assays in Chinese hamster ovary cells transfected with this receptor. Indeed, compared with other agonists, EISAI-1 presented lower relative potency toward inositol 1,4,5-trisphosphate production than toward cAMP accumulation, guanosine 5Ј-O -(3-[35 S]thio)triphosphate binding, and [3 H]arachidonic acid production. These results indicated pathway-dependent differences in EISAI-1 intrinsic efficacies, favoring activations of G s -and G i/o -related pathways over the G q/11 -related pathway. Moreover, although coupling to G q/11 and G i/o involved the third intracellular loop and the C-terminal domain of the NTS1 receptor, respectively, we demonstrated that deletion of the latter domain suppressed agonist-induced cAMP accumulation, suggesting that this domain also mediated coupling to G s . Together, these results indicated that, unlike other agonists, EISAI-1 discriminated between the pathways involving the receptor C-terminal domain and that involving the third intracellular loop. These properties of EISAI-1 were also observed in cortical neurons endogenously expressing the NTS1 receptor. They were further attributed to the functionalization of its COOH end by an ethyl group, because the unesterified analog EISAI-2 presented normal behavior on inositol 1,4,5-trisphosphate production.These findings support the hypothesis of agonist-selective receptor states with distinct conformations or accessibilities of intracellular domains. They also suggest that the differential involvement of these domains in coupling to G proteins might represent a molecular basis for agonist-selective responses through G protein-coupled receptors.It is now well established that a single G protein-coupled receptor (GPCR) can interact with several G proteins or other transducing molecules, thereby activating multiple signaling pathways. Moreover, several studies revealed that a ligand could show differential abilities to trigger these pathways (Kenakin, 1996(Kenakin, , 2001Berg et al., 1998;Brink et al., 2000;Wenzel-Seifert and Seifert, 2000). One important implication of this finding is the possibility of developing drugs acting selectively on one of the responses associated to a receptor.Essentially two mechanisms could lead to agonist-selective activation of effector pathways: differential strength of signaling and agonist-directed trafficking of receptor stimulus (Kenakin, 1995). The first mechanism relies on differential tightness of coupling between the receptor and the various transducing molecules. Agonists of high efficacy will thus induce a pleiotropic response, whereas agonists of low efficacy will trigger only the most efficiently coupled pathway. The second mechanism relies on pathway-dependent differences in agonist intrinsic efficacies. This mec...

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“…Activation of rat NTR1 (rNTR1) induces an increase in inositol trisphosphate (IP 3 ) and Ca 2+ mobilization through an activation of G q/11 (Watson et al 1992, Chabry et al 1994, Hermans et al 1994. It has also been reported that stimulation of NTR1 evokes the production of arachidonic acid and cAMP through G i/o and G s activation respectively (Yamada et al 1993, Carraway & Mitra 1998, Gailly et al 2000. Furthermore, levocabastine and SR 48692 trigger Ca 2+ mobilization, IP production, arachidonic acid release and mitogenactivated protein kinase activity in CHO cells expressing rNTR2 or hNTR2 , Yamada et al 1998.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and functional characterization of a type-I neurotensin receptor (NTR) and a novel NTR from the bullfrog brain

Li¹,

Sicard²,

salam³

et al. 2005

Journal of Molecular Endocrinology

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Neurotensin (NT) is a tridecapeptide that functions as a neurotransmitter and neuromodulator in the nervous system. To date, three different types of NT receptor (NTR), NTR1, NTR2 and NTR3, have been identified only in mammalian species. In the present study we isolated the cDNAs for an NTR1 and a novel NTR in the bullfrog brain, designated bfNTR1 and bfNTR4 respectively. bfNTR1 and bfNTR4 encode 422-and 399-amino acid residue proteins respectively. bfNTR1 has a 64% amino acid identity with mammalian NTR1, and 34-37% identity with mammalian NTR2. bfNTR4 exhibits 43% and 45-47% identity with mammalian NTR1 and NTR2 respectively. Both receptors are mainly expressed in the brain and pituitary. bfNTR1 triggers both CRE-luc, a protein kinase A (PKA)-specific reporter, and c-fos-luc, a PKC-specific reporter, activities, indicating that bfNTR1 can activate PKA-and PKC-linked signaling pathways. However, bfNTR4 appears to be preferentially coupled to the PKA-linked pathway as it induces a higher CRE-luc activity than c-fos-luc activity. bfNTRs exhibit different pharmacological properties as compared with mammalian NTRs. Mammalian NTR1 but not NTR2 responds to NT, whereas both bfNTR1 and bfNTR4 show a high sensitivity to NT. SR 48692 and SR 142948A, antagonists for mammalian NTR1 but agonists for mammalian NTR2, function as antagonists for both bfNTR1 and bfNTR4. In conclusion, this report provides the first molecular, pharmacological and functional characterization of two NTRs in a non-mammalian vertebrate. These data should help to elucidate the phylogenetic history of the G protein-coupled NTRs in the vertebrate lineage as well as the structural features that determine their pharmacological properties.

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Evidence for the dual coupling of the rat neurotensin receptor with pertussis toxin‐sensitive and insensitive G‐proteins

Cited by 28 publications

References 43 publications

Interactions between neurotensin receptors and G proteins

Interactions between neurotensin receptors and G proteins

Differential Involvement of Intracellular Domains of the Rat NTS1 Neurotensin Receptor in Coupling to G Proteins: A Molecular Basis for Agonist-Directed Trafficking of Receptor Stimulus

Molecular cloning and functional characterization of a type-I neurotensin receptor (NTR) and a novel NTR from the bullfrog brain

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