The two-state model of receptor activation

Leff, P.

doi:10.1016/s0165-6147(00)88989-0

Cited by 487 publications

(395 citation statements)

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“…According to the two-state model of receptor activation, the two parameters, ICs0 and maximal response, are dependent on the level of constitutive activity of receptor. As the percentage of constitutive activity increases, the value of ICs0 decreases and the level of maximal response increases [19]. Variation of the two parameters of three EP3 receptor isoforms are consistent with the diversity of constitutive Gi activities of the receptors.…”

Section: Plls0014-5793(96)00354-7supporting

confidence: 66%

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

1996

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We recently demonstrated that two exclusively Gicoupled isoforms of the mouse EP3 receptor, EP3a and 13, with different carboxyl-terminal tails, differed in agonist-independent constitutive Gi activity, and the carboxyl-terminal tail-truncated receptor showed full constitutive activity (Hasegawa, H., Negishi, M., and Ichikawa, A. (1996) J. Biol. Chem. 271, 1857-1860). Here we further examined Gi and Gs activities of the third isoform, EP3T, coupled to both Gi and Gs. The EP3 T receptor showed mostly full constitutive Gi activity and agonistdependent Gs activity. The truncated receptor also showed agonist-dependent Gs activity, but the level was lower than that of the EP3T receptor. Thus, the carboxyl-terminal tail would differentially regulate Gi and Gs activities of the EP3 receptor.

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Section: Plls0014-5793(96)00354-7supporting

confidence: 66%

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

1996

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“…Overall, our data are consistent with the predictions of the classic ternary complex and two-state models of agonist action (Leff, 1995). According to the classic ternary complex model, efficacy is related to the ratio of the affinities of a ligand for the two forms of the receptor (R and RG) and therefore reflects the ability of a ligand to promote (or induce) the formation of the HRG complex (where H is hormone, R is receptor, and G is G protein).…”

Section: Discussionsupporting

confidence: 87%

“…A basic assumption of these models is that there is a direct relationship between the capacity of a drug to induce (or stabilize) an active conformation of a receptor and its ability to elicit a response. This is a basic tenet of the classic ternary complex model (see, e.g., De Lean et al, 1980) as well as more recent models of agonist action that incorporate newer concepts of inverse agonism and agonist-specific states of a receptor (Kenakin, 199%;Leff, 1995;Leff et al, 1997;Surya et al, 1998). For example, the modern two-state model of agonist action (Samama et al, 1993;Leff, 1995) suggests that ligands that bind the receptor with higher affinity for the coupled (active, R*) rather than uncoupled (inactive, R) forms of the receptor are demonstrable agonists, whereas ligands exhibiting converse preferences are inverse agonists.…”

mentioning

confidence: 99%

High‐Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5‐HT_2A and 5‐HT_2C Receptors: Evidence Favoring the Ternary Complex and Two‐State Models of Agonist Action

Fitzgerald

Conklin

Krause

et al. 1999

Journal of Neurochemistry

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Many modern models of receptor-G protein function assume that there is a direct relationship between high-affinity agonist binding and efficacy. The validity of this assumption has been recently questioned for the serotonin 5-HT2, receptor. We examined the intrinsic activities of various ligands in activating phosphoinositide hydrolysis and measured their respective binding affinities to the high-and low-affinity states of the 5-HTzC (VNV isoform) and 5-HT2, receptors. Ligand binding affinities for the high-affinity state of the receptors were determined using 1 -(4-[1251]iodo-2,5-dimethoxyphenyl)-2-aminopropane, whereas rH]mesulergine and N-rH]-methylspiperone were used, in the presence of excess guanine nucleotide [guanosine 5'-0-(3-thiotriphosphate)], to define binding to the low-affinity state of the 5-HTzc and 5-HT2, receptors, respectively. Antagonists labeled the high-and low-affinity states of each receptor with comparable affinities. Previously identified inverse agonists of the 5-HT2, receptor behaved as silent antagonists in our systems even when the receptor was overexpressed at a relatively high density. In contrast, the ability of agonists to bind differentially to the high-and low-affinity states of the 5-HT2, and 5-HT2, receptors was highly correlated (r2 = 0.86 and 0.96, respectively) with their intrinsic activities. These data suggest that high-affinity agonist states can account for agonist efficacy at human 5-HTz, or 5-HTz, receptors without the need for considering additional transition or active states of the receptor-ligand complex. The procedure described herein may expedite drug discovery efforts by predicting intrinsic activities of ligands solely from ligand binding assays.

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“…However, quantification of the D2 receptor family has limitations, because as antagonists these ligands bind with equal affinity to both the high (DRD2 HIGH ) and the low (DRD2 LOW ) affinity states of the DRD2. The DRD2 HIGH primarily mediate the effects of dopamine (George et al, 1985;Leff, 1995;Liu et al, 2000). In addition, the PET/SPECT signal from these radioligands consists of a mix of DRD2 and DRD3 binding (Halldin et al, 1995;Mukherjee et al, 1999;Narendran et al, 2006;Strange, 2001;Videbaek et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

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The two-state model of receptor activation

Cited by 487 publications

References 3 publications

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

High‐Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5‐HT_2A and 5‐HT_2C Receptors: Evidence Favoring the Ternary Complex and Two‐State Models of Agonist Action

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

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The two-state model of receptor activation

Cited by 487 publications

References 3 publications

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

Prostaglandin E receptor EP3γ isoform, with mostly full constitutive Gi activity and agonist‐dependent Gs activity

High‐Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5‐HT2A and 5‐HT2C Receptors: Evidence Favoring the Ternary Complex and Two‐State Models of Agonist Action

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

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High‐Affinity Agonist Binding Correlates with Efficacy (Intrinsic Activity) at the Human Serotonin 5‐HT_2A and 5‐HT_2C Receptors: Evidence Favoring the Ternary Complex and Two‐State Models of Agonist Action