Characterisation of agonist binding on human 5-HT2C receptor isoforms

Quirk, Kathleen; Lawrence, A. J.; Jones, J A; Misra, Anil Kumar; Harvey, Victoria L.; Lamb, Helen; Revell, Dean F.; Porter, Richard H.; Knight, Antony R.

doi:10.1016/s0014-2999(01)00943-8

Cited by 25 publications

(13 citation statements)

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“…In these brains, 5-HT 2C receptor isoforms with reduced function were expressed at significantly increased levels, suggesting that the regulation of editing by synaptic 5-HT is defective [84]. Decreased agonist binding affinity has also been linked to RNA editing, however antagonist binding remained unaltered [85].…”

Section: -Ht 2c Receptor Structure Signal Trans-duction and Pharmacmentioning

confidence: 99%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

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Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT 2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.Keywords: Serotonergic receptors, Depression, Schizophrenia, Drug of abuse, selective 5-HT 2C drugs. BASIC ANATOMY OF 5-HT SYSTEMMore than fifty years have passed since Twarog and Page [1] isolated an indole, identified as serotonin (5-HT), in the mammalian brain. Subsequently, Brodie and colleagues [2] suggested that 5-HT might serve as a neurotransmitter in the central nervous system (CNS). The result was one of the most important discoveries in science, giving birth to a new branch of neuroscience [3]. Serotonin is one of the oldest biologically active compound on earth, found in a variety of plants and animals. In vertebrates, the majority of the neurons containing 5-HT are grouped in 9 nuclei named B1 to B9, located in the medial part of the brainstem, generically called the raphe nuclei [4] (Fig. 1). These midline clusters can be divided into two major groups. The caudal or inferior group, localized in the medulla, contains the three nuclei projecting essentially to the grey matter of the spinal cord: the nucleus raphe magnus (NRM, cell group B5), nucleus raphe obscurus (NRO, cell groups B1-B2-B3), and nucleus raphe pallidus (NRP, cell group B4). The rostral or superior group, situated in the pons/mesenchephalon, contains the dorsal raphe nucleus (DRN, cell groups B6 and B7) and the median raphe nucleus (MRN, cell group B8). These nuclei supply about 80% of the serotonergic innervation of the forebrain. Even if in many brain areas, the innervation coming from the two nuclei overlaps, in certain regions the innervation comes exclusively or prevalently from one nucleus only. For example, the dorsal hippocampus receives a serotonergic innervation only from MRN, other areas innervated preferentially from this nucleus are: the medial preoptic area, the suprachiasmatic nucleus, the olfactory bulb *Address correspondence to this author at the Istituto di Ricerche Farmacologiche "Mario Negri", Consor...

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Section: -Ht 2c Receptor Structure Signal Trans-duction and Pharmacmentioning

confidence: 99%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

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“…Interestingly, Ro60,0175 also markedly activated Gq/11 in frontal cortex. This compound was originally described as a selective 5-HT 2C receptor agonist (Boes et al, 1997;Cussac et al, 2002a;Porter et al, 1999;Quirk et al, 2001), but its selectivity for these receptors has been contested and Ro60,0175 behaves as a full agonist at 5-HT 2B receptors both in rat brain and in CHO cell lines (Cussac et al, 2002b;Martin et al, 1998;Porter et al, 1999). Clearly, as further discussed in following text, the present data show that Ro,60,175 engages cerebral populations of 5-HT 2A receptors, albeit at concentrations higher than those stimulating 5-HT 2B and 5-HT 2C sites (Cussac et al, 2002b).…”

Section: Discussion Evidence For Activation Of Gq/11 By 5-ht Doi Andmentioning

confidence: 99%

“…All classes of 5-HT 2 receptors are characterized by relatively low affinity for 5-HT as compared to the 5-HT 2A/2C receptor agonist and hallucinogen DOI (Barnes and Sharp, 1999). Interestingly, the indoline derivative Ro60,0175 has been extensively used as an agonist of 5-HT 2C (and 5-HT 2B ) sites (Boes et al, 1997;Martin et al, 1998;Porter et al, 1999;Quirk et al, 2001). Certain functional studies indicate that it may also stimulate 5-HT 2A receptors (Cussac et al, 2002b).…”

Section: Introductionmentioning

confidence: 99%

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Cour

Chaput

Touzard

et al. 2008

Synapse

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Though transduction mechanisms recruited by heterologously expressed 5-HT 2A receptors have been extensively studied, their interaction with specific subtypes of G-protein remains to be directly evaluated in cerebral tissue. Herein, as shown by an immunocapture/scintillation proximity analysis, 5-HT, the prototypical 5-HT 2A agonist, DOI, and Ro60,0175 all enhanced [ 35 S]GTPgS binding to Gaq/11 in rat cortex with pEC 50 values of 6.22, 7.24 and 6.35, respectively. No activation of Go or Gs/olf was seen at equivalent concentrations of DOI. Stimulation of Gaq/11 by 5-HT (30 lM) and DOI (30 lM) was abolished by the selective 5-HT 2A vs. 5-HT 2C /5-HT 2B antagonists, ketanserin (pK B values of 9.11 and 8.88, respectively) and MDL100,907 (9.82 and 9.68). By contrast, 5-HT-induced [ 35 S]GTPgS binding to Gaq/11 was only weakly inhibited by the preferential 5-HT 2C receptor antagonists, RS102,221 (6.94) and SB242,084 (7.39), and the preferential 5-HT 2B receptor antagonist, LY266,097 (6.66). The antipsychotic, clozapine, which had marked affinity for 5-HT 2A receptors, blocked the recruitment of Gaq/11 by 5-HT and DOI with pK B values of 8.54 and 8.14, respectively. Its actions were mimicked by the ''atypical'' antidepressant and 5-HT 2A receptor antagonist, mirtazapine, which likewise blocked 5-HT and DOI-induced Gaq/ 11 protein activation with pK B values of 7.90 and 7.76, respectively. In conclusion, by use of an immunocapture/scintillation proximity strategy, this study shows that native 5-HT 2A receptors in rat frontal cortex specifically recruit Gaq/11 and that this action is blocked by clozapine and mirtazapine. Quantification of 5-HT 2A receptor-mediated Gaq/11 activation in frontal cortex should prove instructive in characterizing the actions of diverse classes of psychotropic agent.

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“…We trained three separate groups of pigeons to discriminate one of the following drugs from saline: MK212, an agonist (Quirk et al 2001); methysergide, a neutral antagonist (Barker et al 1994;Herrick-Davis et al 1997); or mianserin, an inverse agonist (Barker et al 1994;Devlin et al 2004;Schlag et al 2004). A range of additional compounds with varying intrinsic efficacies measured in vitro were examined for substitution or combination: agonists mCPP (Quirk et al 2001;Schlag et al 2004) and WAY-163909 (Dunlop et al 2005;Marquis et al 2007); neutral antagonists 2-bromo-(+)-lysergic acid diethylamide (BOL; Barker et al 1994) and potentially metergoline (Bray and Goddard 2008;Cussac et al 2002;Labrecque et al 1995); and inverse agonists SB206,553 (Chanrion et al 2008;Marion et al 2004), ketanserin (Barker et al 1994), and cyproheptadine (Barker et al 1994).…”

mentioning

confidence: 99%