Molecular biology of 5-HT receptors

doi:10.1016/0165-6147(89)90080-1

Trends in Pharmacological Sciences

Volume 10, Issue 2, February 1989, Pages 64-69

https://doi.org/10.1016/0165-6147(89)90080-1 Get rights and content

Abstract

Within the past six months, isolation of cDNA or genomic clones has been reported for three 5-HT receptors, the 5-HT_1C, 5-HT_1A and 5-HT₂ subtypes. As members of the G protein receptor superfamily, all three 5-HT receptor clones encode single-subunit proteins containing approximately 450 amino acids arrayed as seven interconnected transmembrane segments. Comparisons of 5-HT receptor sequence data with data from other G protein receptors provide suggestions for which amino acids may be involved in the binding of 5-HT and 5-HT antagonists to these receptors, and for certain key amino acids which may help confer 5-HT properties on these receptors. These rapid advances in our molecular understanding of 5-HT receptors also have significant implications for the ongoing debate over 5-HT receptor classification. In this article, Paul Hartig assembles the available molecular data and proposes a speculative model for the structure of G protein-coupled 5-HT receptors.

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Tachyphylaxis to 5-HT<inf>3</inf>-receptor-mediated activation of vagal afferents is prevented by co-activation of 5-HT<inf>2</inf> receptors
2006, Brain Research
Citation Excerpt :
The α-methyl-5-HT-induced pressor responses were accompanied by falls in HR and CO which were most likely due to baroreceptor-reflex-mediated changes in cardiac sympathetic and parasympathetic nerve activity (see Lewis et al., 1989a,b; Jacob et al., 1991). 5-HT2Rs exist on perikarya and nerve terminals of vagal afferent neurons (Fozard, 1990; Glaum et al., 1988; Goudie and Lathley, 1990; Hartig, 1992; Pritchett et al.; Probst et al., 1992). This study provides evidence that 5-HT2Rs are present on cardiopulmonary vagal afferents mediating the BJR (see below), although it is evident that the stimulation of these receptors does not activate these afferents.
Functional studies have provided evidence that 5-HT₃ ion-channel receptors (5-HT₃Rs) on vagal cardiopulmonary afferents mediating the Bezold–Jarisch reflex (BJR) rapidly desensitize upon repeated exposure to selective 5-HT₃R agonists. G-protein-coupled 5-HT₂ receptors (5-HT₂Rs) also exist on vagal afferents, although activation of these receptors does not elicit the BJR. However, there is in vivo evidence that 5-HT₂Rs may regulate the activity of 5-HT₃Rs. The aim of this study was to determine whether co-activation of 5-HT₂Rs prevents desensitization of 5-HT₃Rs mediating the BJR in conscious rats. The principal findings were that (1) tachyphylaxis rapidly developed to the BJR-mediated hemodynamic responses elicited by successive injections of 5-HT₃R agonists and (2) co-injection of the selective 5-HT₂R agonist, α-methyl-5-HT, prevented tachyphylaxis to the BJR-mediated hemodynamic responses elicited by the 5-HT₃R agonists. Additional studies provided evidence that (1) tachyphylaxis to the 5-HT₃R agonists was not due to impairment of the central or efferent processing of the BJR, and (2) the pressor responses elicited by α-methyl-5-HT were not responsible for preventing tachyphylaxis to the BJR reflex responses elicited by 5-HT₃R agonists. These results suggest that the loss of response to 5-HT₃R agonists is due to desensitization of 5-HT₃Rs on vagal afferents mediating the BJR and that co-activation of 5-HT₂Rs prevents the desensitization of these 5-HT₃Rs.
Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT<inf>1A/1B/2C</inf> receptors
2003, Pharmacology Biochemistry and Behavior
Indorenate (5-methoxytryptamine β-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT_1A/1B/2C receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT_1A/1B/2C agonists, but not those of 5-HT_3/4 agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT_1A/1B/2C receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT_1A, 5-HT_1B, 5-HT_2C, and 5-HT_3/4 receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D⁺S⁻, administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D⁻S⁺ had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT_1A), NAN190 (5-HT_1A), methiothepin (5-HT_1A/1B/2C), GR127935 (5-HT_1B/1D), ketanserin (5-HT_2A/2C), ritanserin (5-HT_2C/2A), mesulergine (5-HT_2C/2A), metergoline (5-HT_2C/2A), SB206553 (5-HT_2B/2C), and tropisetron (5-HT_3/4). In Group D⁺S⁻, the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine≅SB206553>metergoline>methiothepin>NAN190, while in Group D⁻S⁺, the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine≅SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT_1A/2C/1B receptors and that blockade of any of its components produces a degradation of its discriminative effects.
Distribution and characterization of [ <sup>3</sup> H]mesulergine binding in human brain postmortem
1999, European Neuropsychopharmacology
Much interest is currently being directed towards serotonin (5-HT) receptors of type 2C (5-HT_2C) because of their possible involvement in the control of different activities, such as the composition of the cerebrospinal fluid, locomotion, feeding, neuronal excitability and anxiety. The limited information regarding their distribution in the human brain prompted us to investigate, and to characterize the binding of [³H]mesulergine, a HT_2C antagonist, in autopsy samples from 24 subjects.
The results showed that the [³H]mesulergine binding represented 95% of the total binding and equilibrium saturation binding experiments resulted in a single straight line, consistent with the presence of one site only. The area with the highest density of [³H]mesulergine binding was the choroid plexus, followed at a significantly lower level by the hippocampus, substantia nigra, basal ganglia, amygdala, hypothalamus and prefrontal cortex. The pharmacological profile of the [³H]mesulergine binding was consistent with that of 5-HT_2C receptors, since the most effective displacers were ritanserin, mesulergine and mianserine, followed by clozapine, ketanserine and m-CPP, while other compounds had a negligible or no effect.
These findings, showing a wide distribution of [³H]mesulergine binding sites in the human brain, could provide anatomical bases for the different functions attributable to 5-HT_2C receptors in humans.
5(10→9)abeo-ergoline derivatives: Synthesis, 5-HT(1A)-receptor affinity and selectivity
1998, European Journal of Medicinal Chemistry
The synthesis and the structure-affinity relationship (S.A.F.I.R.) study for the 5-HT_1A receptor sites of a novel series of 5(10→9)abeo-ergoline derivatives are presented. Most derivatives showed moderate to high affinity and selectivity for 5-HT_1A receptor sites. The structure-affinity relationship pointed out the role of the substituent at position 8, and the outstanding importance of the reduction of the indole 2,3-double bond for achieving the highest 5-HT_1A affinity and selectivity within the compounds presented.
Role of central neural mechanisms in the regulation of hepatic glucose metabolism
1997, Life Sciences
Central monoamine neurotransmitters affect blood glucose homeostasis. Activation of central cholinergic, noradrenergic histaminergic, and serotonergic neurons rapidly increase hepatic glucose output via the sympathetic nervous system. Acute hyperglycemia is mediated by three distinct pathways: the action of epinephrine on the liver, the action of glucagon on the liver, and the direct innervation of the liver. The relative contribution of these factors to hyperglycemia can be altered by diet and the kinds of neurotransmitters evoked in the central nervous system, but the magnitude of epinephrine secretion is closely related to the magnitude of hyperglycemia. On the other hand, neuropharma-cological stimulation of central cholinergic muscarinic receptors, histaminergic H₁ receptors, and serotonergic 5-HT₂ receptors increases hypothalamic noradrenergic neuronal activity, which is associated with hyperglycemia. In contrast, central GABA_A receptors play an inhibitory role in the regulation of hepatic glucose metabolism. Thus, central monoaminergic neurons could be linked together, and play a homeostatic role in the regulation of hepatic glucose metabolism.
5-HT<inf>3</inf> receptors: A potential therapeutic target for epilepsy
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Molecular biology of 5-HT receptors