Serotonin receptor families

Members of all serotonin receptor families except the 5-HTg receptor (Hamon et al. 1999 Marcos et al. 2006) occur presynaptically. Presynaptic 5-HT3 receptors are discussed in this Handbook in the chapter on ionotropic receptors by Dorostkar and Boehm. 

PucadyU TJ, Kalipatnapu S, Chattopadhyay A. The serotoninlA receptor a representative member of the serotonin receptor family. Cell Mol Neurobiol. 2005 25(3-4) 553-580. 

Liebmarm T, Kruusmagi M, Soimal-Bassillious N et al (2012) A noncanonical postsynaptic transport route for a GPCR belonging to the serotonin receptor family. J Neurosci 32 17998-18008... 

Saudou, F., Boschert, U Amlaiky, N Plassat, J. L and Hen, R. (1992). A family of Drosophila serotonin receptors with distinct intracellular signalling properties and expression patterns. EMBO J. 11 7-17. 

Pompeiano, M., Palacios, J. M. Mengod, G. (1994). Distribution of the serotonin 5-HT2 receptor family mRNAs comparison between 5-HT2a and 5-HT2C receptors. Molec. Brain Res. 23, 163-78. 

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. 

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]. 

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. 

At least 18 different serotonin receptors, divided into numerous families. 

Wang HY, Friedman E Chronic lithium desensitization of autoreceptors mediating serotonin release. Psychopharmacology 94 312-314, 1988 Wang HY, Friedman E Lithium inhibition of protein kinase C activation-induced serotonin release. Psychopharmacology 99 213-218, 1989 Wank SA, Pisegna JR, de Weerth A Brain and gastrointestinal cholecystokinin receptor family structure and functional expression. Proc Natl Acad Sci USA 89 8691-8695, 1992... 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

With respect to a specific and common clinical problem, advice to withdraw hypnotic medication should follow a careful evaluation of self-reported sleep patterns, psychological factors and psychosocial status. Ambulant monitoring can be helpful in patients who have encountered severe problems in effecting withdrawal. A careful psychiatric assessment should be made to ascertain whether the patient has clinically significant anxiety and/or depression. Both should be treated with a selective serotonin receptor inhibitor (SSRI) before withdrawal from the hypnotic is attempted. An optimal tapering schedule should be discussed with the patient some will attempt a rapid withdrawal over less than 8 weeks and others will require much longer. This is particularly so if previous attempts to withdraw have been unsuccessful. Carers, family and friends should be mobilized to help in withdrawal, should the patient wish this. Substitution of zolpidem may facilitate withdrawal but should be kept as a reserve strategy. 

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. 

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). 

Julius D, Huang KN, Livelli TJ, Axel R, Jessell TM. The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors. Proc Natl Acad Sci USA 1990 87 928-932. 

Matthes H, Boschert U, Amlaiky N, et al. Mouse 5-hydroxytiyptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors cloning, functional expression, and chromosomal localization. Mol Pharmacol 1993 43 313-319. 

Murad I, et al. A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia. Am J Med Genet 2001 105(3) 236—238. 

The 5-HT1A receptor is a member of the 5-HT] family of serotonin receptors best known for their capacity to inhibit adenylyl cyclase activity via pertussis toxin-sensitive G proteins. These receptors also couple to K+ channels, Ca2+ channels, PLC, intracellular calcium, mitogen-activated protein kinase cascade, and Na+/K+-ATPase (73,74). This receptor is an important target for the management of anxiety, depression, and schizophrenia (75-78). 

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