G-protein-coupled serotonin

FI6URE 2—4. G-protein-coupled serotonin (5-HT) receptors that inhibit... 

Molecular Biology and Genomic Organization of G Protein-Coupled Serotonin Receptors... 

The G protein-coupled serotonin (5-hydroxytryptamine 5-HT) receptors are typical group A rhodopsin-like G protein-coupled receptors (GPCRs) in that they are predicted to possess seven transmembrane spanning helices, three intracellular and three extracellular loops, an extracellular amino-terminus, and... 

The purpose of this review is to examine experimental information concerning the structure and function of the G protein-coupled serotonin receptors in the three-dimensional context provided by the structure of rhodopsin. A critical examination of the suitability of rhodopsin as a template for serotonin receptor modeling from the level of sequence alignment to interpretation of biochemical experiments of relevance to the issues of structure-function relationships is presented. 

Andrade R, Malenka RC, Nicoll RA. A G protein couples serotonin and GABAb receptors to the same channel in hippocampus. Science 1986 234 1261-1265. 

Serotonin agonists G-protein coupled 5-HT receptors 5-HT3 ion channels cAMP (5-HT-,) t cAMP (5-HT4 7) t PLC (5-HT2) l Release of excitatory neuropeptides l Neurogenic inflammation f vasoconstriction Myocardial infarction, stroke, peripheral vascular occlusion... 

Enterochromaffin cells are interspersed with mucosal cells mainly in the stomach and small intestine. In the blood, serotonin is present at high concentrations in platelets, which take up serotonin from the plasma by an active transport process. Serotonin is released on platelet activation. In the central nervous system, serotonin serves as a transmitter. The main serotonin-containing neurons are those clustered in form of the Raphe nuclei. Serotonin exerts its biological effects through the activation of specific receptors. Most of them are G-protein coupled receptors (GPCRs) and belong to the 5-HTr, 5-HT2-, 5-HT4-, 5-HTs-, 5-HT6-, 5-HT7-receptor subfamilies. The 5-HT3-receptor is a ligand-operated ion channel. 

Three families of serotonin receptor, the 5-HT family, the 5-HT2 family and the family that includes the 5-HT4, 5-ht6 and 5-HT7 receptors represent the three major classes of 5-HT receptor that are G-protein-coupled receptors (Ch. 19). The 5-HT3 receptor is a ligand-gated ion channel and is a separate family. Although each serotonin receptor can be potently activated by 5-HT, differences insignal transduction mechanisms,neuroanatomical distribution and affinities for synthetic chemicals create opportunities for drug discovery and make each 5-HT receptor subtype a potential therapeutic target. 

Membrane-associated receptors are linked to transducing proteins (like G-proteins) in the inner portion of the membrane. G-protein coupled receptor (GPCR) families comprise a major class of the receptors that are pharmacologically relevant, such as muscarinic acetyl choline receptors, adrenoceptors, dopamine receptors, serotonine, opiate, peptide hormone, purinerg receptors, and also sensory chemoreceptors. A large variety of subtypes are described in the pharmacological literature. 

G-protein coupled receptor family comprises most well-known cell surface receptors including the major drug targets, as previously stated. Early PAL results have been reviewed in several papers, and book chapters. For opiate, NMDA, sigma, benzodiazepine, GABA, acetyl choline, and adrenerg, serotonine receptors see [52,59,60], and for purinerg, histamine, and dopamine receptors see [61]. 

The 5-HT4 receptor is a member of the seven transmembrane-spanning G protein-coupled family of receptors (GPCR) and constitutes an important subtype of the class of serotonin (5-HT) receptors. Initially, the 5-HT4 receptor was characterized in the neuronal cell culture [3] of mouse colliculi and was shown to be positively coupled to adenylyl cyclase. The effect of serotonin was mimicked by the 5-HT4 receptor agonists, BIMU 1 and BIMU 8, and was blocked by the 5-HT4... 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

Serotonin receptors. Based on biochemical and pharmacological criteria seven receptor classes can be distinguished. Of major pharmacotherapeutic importance are those designated 5-HTi, 5-HT2,5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated non-selective cation channel. 

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

Serotonin is involved in a number of diverse activities, including an important role in emesis. Four main subtypes of 5-HT receptor have been discovered, each having specific roles. The 5-HT3 receptor is a ligand-gated ion channel similar to the muscarinic acetylcholine receptor, whereas 5-HTl, 5-HT2 and 5-HT4 are G protein-coupled receptors. 5-HT3 receptors are located both pre-and postsynaptically on neurones in the central and peripheral nervous systems. In the CNS they are present in high concentrations in the area postrema, and peripherally in the upper GIT. 

HTxR, serotonin receptor CB1R, cannabinoid-1 DAT, dopamine transporter GABA, y-aminobutyric acid Kir3 channels, G protein-coupled inwardly rectifying potassium channels LSD, lysergic acid diethylamide i -OR, H-opioid receptor nAChR, nicotinic acetylcholine receptor NET, norepinephrine transporter NMDAR, N -methyl-D-aspartate receptor SERT, serotonin transporter VMAT, vesicular monoamine transporter indicates data not available. 

Antihistamines are antagonists of histamine receptors that displace histamine competitively from its receptors and block the effects of histamine. Histamine receptors, in turn, are G-protein-coupled receptors (GPCRs) that contain the typical seven-transmembrane loop motif. Other common GPCRs include calcium channel receptors, andrenergic ai, dopamine D2, serotonin 5-HT2 and muscarinic receptors. They have... 

HT interacts with a large diversity of G-protein-coupled receptors, namely the 5-HTi,2,4,5,6 and 7 families, and in addition with a ligand-gated cationic channel, 5-HT3. The diversity has been explained by the fact that serotonin is one of the oldest neurotransmitters in evolution. The 5-HTi receptor family (5-HTia,ib,id,ie andiF) couples mainly to Gi/o. 5-1 I I oa, 5-HT2B and 5-HT2C receptors couple to Gq/11. 5-HT4, 5-HT6, and 5-HT7 receptors couple to Gs. The 5-HT5A receptor couples principally to Gi/o. The 5-HTsb receptor seems to occur only in rodents, and no transduction mechanism has been identified. 

If presynaptic histamine receptors are more uniform than presynaptic dopamine receptors, the contrary holds true for presynaptic serotonin receptors they are even more diverse than presynaptic dopamine receptors. As mentioned in the Introduction, presynaptic 5-HT3 receptors, being ligand-gated ion channels, are covered in the chapter by Dorostkar and Boehm and will be mentioned here only occasionally. Presynaptic G protein-coupled 5-HT receptors inhibit the release of serotonin from serotonergic axon terminals and inhibit or enhance the release of other neurotransmitters (Table 4). 

Among the seven families of serotonin receptors, only the 5-HT3 receptors are ligand-gated ion channels, whereas all others are G protein-coupled receptors (Barnes and Sharp 1999). 5-HT3 receptors are rather unselective cation channels with a high permeability for Ca2+ (Ronde and Nichols 1998). In the central nervous system, they are expressed abundantly in the neocortex, the anterior olfactory nucleus, the hippocampus, and the amygdala. In addition, 5-HT3 receptors are present in the caudate putamen and the nucleus accumbens, and, at high levels, in the brain stem (Parker et al. 1996 Morales et al. 1998 Chameau and van Hooft 2006). 

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