Evidence for protean agonism of RX 831003 at α2A-adrenoceptors by co-expression with different Gα protein subunits

Pauwels, Petrus J.; Rauly, Isabelle; Wurch, Thierry; Colpaert, Françis C.

doi:10.1016/s0028-3908(01)00201-5

Cited by 22 publications

(11 citation statements)

References 24 publications

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“…Multiple receptor conformational states are also evident in single molecule spectroscopy studies of the ␤2-adrenergic receptor (11) and are supported by the presence of phenotypically different serotonin 5HT2C receptor activation mutants (12). Pharmacological evidence for signal trafficking has been reported in several heptahelical receptors (14,15,66,67). Evidence for signal trafficking at the D 2 receptor based on the G-protein sensitivity of binding affinity has been previously reported for D 2 receptor expressing Sf21 insect cell lines.…”

Section: Translocation and Phosphorylation Of Akt By D 2 Receptormentioning

confidence: 89%

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Nair

Sealfon

2003

Journal of Biological Chemistry

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Section: Translocation and Phosphorylation Of Akt By D 2 Receptormentioning

confidence: 89%

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Nair

Sealfon

2003

Journal of Biological Chemistry

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“…For the ␣ 2A -AR, two signaling pathways were generated by transfection of two Gproteins, a calcium response mediated by a promiscuous G␣15 protein and a pertussis toxin-resistant [ 35 S]GTP␥S binding response mediated by a mutant G␣o Cys351Ile protein. The ligand RX 831003 behaved as a protean agonist, and its activity was highly dependent on the coexpressed G␣ protein subunit (Pauwels et al, 2002). Agonist-induced trafficking of the rat neurotensin receptor 1 (NTS1) revealed a reverse potency order between two agonists, EISAI-1 and neuromedin N. The properties of EISAI-1 were also observed in cortical neurons endogenously expressing the NTS1 receptor (Skrzydelski et al, 2003).…”

Section: Transfected Systemsmentioning

confidence: 99%

Multiple Signaling States of G-Protein-Coupled Receptors

2005

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“…It was therefore predicted that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR, depending on the level of constitutive activity. Apparent protean agonism had been observed so far after modification of recombinant receptors (9-13), such as their desensitization or mutation (10,12), or their expression in distinct cells or with different G␣-protein subunits (11,13). However, the process remained to be established for native receptors under physiological conditions.…”

mentioning

confidence: 99%

Protean agonism at histamine H ₃ receptors in vitro and in vivo

Gbahou

Rouleau

Morisset-Lopez

et al. 2003

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

132

103

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G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R*) conformations in equilibrium. R* is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive activity. The existence of another pharmacological entity, referred to as ''protean'' agonists (after Proteus, the Greek god who could change shape), was assumed on theoretical grounds. It was predicted from the existence of constitutive activity that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR. Here, we show that proxyfan, a high-affinity histamine H 3-receptor ligand, acts as a protean agonist at recombinant H 3 receptors expressed in the same Chinese hamster ovary cells. In support of the physiological relevance of the process, we show that proxyfan also behaves as a protean agonist at native H 3 receptors known to display constitutive activity. On neurochemical and behavioral responses in rodents and cats, proxyfan displays a spectrum of activity ranging from full agonism to full inverse agonism. Thus, protean agonism demonstrates the existence of ligand-directed active states LR* different from, and competing with, constitutively active states R* of GPCRs, and defines a pharmacological entity with important therapeutic implications.

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Evidence for protean agonism of RX 831003 at α2A-adrenoceptors by co-expression with different Gα protein subunits

Cited by 22 publications

References 24 publications

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Multiple Signaling States of G-Protein-Coupled Receptors

Protean agonism at histamine H ₃ receptors in vitro and in vivo

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Evidence for protean agonism of RX 831003 at α2A-adrenoceptors by co-expression with different Gα protein subunits

Cited by 22 publications

References 24 publications

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor

Multiple Signaling States of G-Protein-Coupled Receptors

Protean agonism at histamine H 3 receptors in vitro and in vivo

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Product

Resources

About

Protean agonism at histamine H ₃ receptors in vitro and in vivo