Associate editor: B.L. RothMultiplicity of mechanisms of serotonin receptor signal transduction
Introduction
Serotonin (5-HT, 5-hydroxytryptamine) was discovered in 1948 by Rapport et al. as a potent vasotonic factor. For many years, the physiological effects of 5-HT, including its effects on the CNS, were attributed to only two major subtypes of 5-HT receptors (Gaddum & Picarelli, 1957). Because of the development of sophisticated pharmacological tools in the 1980s, it became clear that there must be more than two subtypes of 5-HT receptors. Molecular cloning studies over the last 14 years have confirmed the existence of at least 14 subtypes of 5-HT receptors, each encoded by distinct genes. Splice variants of many of the subtypes have been identified subsequently, resulting in the discovery of at least 30 distinct protein products that recognize 5-HT as their physiological ligand. Most of the receptor genes (13) belong to a large family of receptors that encode proteins that transduce signals through guanine nucleotide binding and regulatory proteins (G-proteins).
The 5-HT receptors have been divided into 7 subfamilies by convention. Those subfamilies have been characterized by overlapping pharmacological properties, amino acid sequences, gene organization, and second messenger coupling pathways (Hoyer et al., 1994). The 5-HT1, 5-HT2, 5-HT4, 5-ht5, 5-HT6, and 5-HT7 receptors couple to G-proteins, whereas the 5-HT3 receptors are 5-HT-gated ion channels. The basic architecture of the G-protein-coupled 5-HT receptors is similar to that proposed for nearly all of the G-protein-coupled receptors (GPCRs). These receptors are integral membrane proteins with 7 putative hydrophobic transmembrane domains connected by 3 intracellular loops (termed i1–i3) and 3 extracellular loops (termed e1–e3). The amino terminus is oriented toward the extracellular space, whereas the carboxyl terminus is oriented toward the cytoplasm. The core proteins also possess conserved or common sites for post-translational modifications. The extracellular domains are typically glycosylated, and possess cysteine residues that may participate in disulfide bonds that provide structural constraints on the conformation of the receptors. The intracellular domains possess sites for interacting with G-proteins and other regulatory proteins, and sites for phosphorylation by diverse serine-threonine kinases. Some of the 5-HT receptors contain PS-95 discs-large ZO-1 interaction motif (PDZ) domains within their intracellular domains. Most of the 5-HT receptors also possess cysteine residues within their carboxyl termini that may be palmitoylated, thus creating potential membrane anchors that can form a putative fourth intracellular loop.
The purpose of this review is to summarize what is known about the second messenger and effector linkages of 5-HT receptors, as revealed in native tissues and cells and in heterologous expression systems. This is a timely and important topic that already has been the subject of many excellent reviews (for example, Hoyer et al., 1994, Boess & Martin, 1994, Zifa & Fillion, 1992, Roth et al., 1998). Recent studies have revealed a rich diversity of coupling mechanisms for each 5-HT receptor subtype. The multiplicity of coupling pathways for each of the receptors suggests that each individual 5-HT receptor subtype can regulate a broad array of potential signals that could be affected by variables such as cell type, receptor number, numbers and types of G-proteins expressed in the target cells, and the specific agonist through which the receptor is activated. This review will focus only upon the signaling linkages of the cloned G-protein-coupled 5-HT receptors. We will not discuss other 5-HT receptors, such as putative peripheral “5-HT1P” receptors (Pan et al., 1997), which have been reviewed elsewhere (Gershon, 1999). The discussion will be organized so that each major receptor subfamily will be discussed individually.
Section snippets
The 5-hydroxytryptamine1 receptors
There are 5 members of the 5-HT1 receptor family, termed 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. A receptor formerly termed the 5-HT1C receptor is no longer felt to be a member of the 5-HT1 receptor family, having been reclassified as the 5-HT2C receptor (Hoyer et al., 1994), based on similarities to other 5-HT2 receptors in structure and second messenger systems. The 5-HT1 receptors couple primarily through Gi/o-proteins to the inhibition of adenylyl cyclase (AC) (see Fig. 1) and to a
The 5-hydroxytryptamine2 receptors
There are three members of the 5-HT2A receptor family, termed 5-HT2A, 5-HT2B, and 5-HT2C (Hoyer et al., 1994). The 5-HT2A receptor is probably the 5-HT M receptor described by Gaddum and Picarelli (1957). The 5-HT2B receptor was formerly referred to as the 5-HT2F receptor [or serotonin receptor like (SRL)] (Foguet et al., 1992b), and the 5-HT2C receptor was previously referred to as the 5-HT1C receptor. The 5-HT2 receptors couple consistently to the PLC-β second messenger pathway (Peroutka,
The 5-hydroxytryptamine4 receptor
Three types of 5-HT receptors couple primarily to the activation of AC: the Gs-coupled 5-HT4, 5-HT6, and 5-HT7 receptors (Hamblin et al., 1998). Unlike the 5-HT6 and 5-HT7 receptors, the 5-HT4 receptor was well-characterized pharmacologically and functionally Dumuis et al., 1988, Bockaert et al., 1990 prior to its cloning. The major functional effects of the 5-HT4 receptors are prokinetic actions in the gut and positive inotropy, chronotropy, and lusitropy in atria, but not ventricles (Kaumann,
The 5-hydroxytryptamine5 receptors
Currently, little is known about 5-ht5 receptors. As functional 5-ht5 receptors have not been identified in vivo yet, the lower case designation is used. Cloning experiments have revealed two subtypes of the 5-ht5 receptor, termed 5-ht5a and 5-ht5b. Both 5-ht5a and 5-ht5b receptors have been cloned from rat and mouse, but only the 5-ht5a receptor has been cloned from human Plassat et al., 1992, Erlander et al., 1993, Matthes et al., 1993, Wisden et al., 1993, Rees et al., 1994. The human 5-ht5A
The 5-hydroxytryptamine6 receptor
Two groups cloned the rat 5-HT6 receptor cDNA in 1993, although there was disagreement over the sequence of this receptor Monsma et al., 1993, Ruat et al., 1993a. This was subsequently resolved as a sequencing error after the cloning of the human 5-HT6 receptor in 1996 (Kohen et al., 1996). The human 5-HT6 receptor is a 440 amino acid protein. The gene contains two introns that correspond to regions of the putative i3 and e3 loops Monsma et al., 1993, Ruat et al., 1993a. The gene for the
The 5-hydroxytryptamine7 receptor
The 5-HT7 receptor is the third 5-HT receptor subtype shown to couple to Gs Bard et al., 1993, Lovenberg et al., 1993a, Plassat et al., 1993, Ruat et al., 1993b, Shen et al., 1993. It is highly expressed in the CNS, especially in the hippocampus, the hypothalamus, and the neocortex. It has been speculated to participate in the control of circadian rhythm because it is expressed in the suprachiasmatic nucleus Lovenberg et al., 1993a, Stowe & Barnes, 1998. The 5-HT7 receptor is also expressed in
Conclusion
The rich diversity of coupling of the 5-HT receptors to distinct (and sometimes opposing) signaling pathways is becoming more broadly appreciated as a mechanism of ‘fine-tuning” receptor response to the requirements of the specific cells and tissues in which they are expressed. The diversity of signaling is mediated by a large number of 5-HT receptors (14 genomically encoded) and their variants (over 20 splice variants or variants resulting from mRNA editing), and also by cell-specific and
Acknowledgements
The authors were supported by grants from the Department of Veterans Affairs (Merit Awards to M.N.G. and J.R.R. and a REAP Award to Y.V.M., A.G., J.R.R., G.C., and M.N.G.), the National Institutes of Health (DK52448 and DK54720 to J.R.R., DK053981 to T.W.G., and DK02694 to Y.V.M.), and a laboratory endowment jointly supported by the M.U.S.C. Division of Nephrology and Dialysis Clinics, Incorporated (J.R.R.). A.G. and M.N.G. were Associate Investigators of the Department of Veterans Affairs
References (419)
- et al.
Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera
Neuropharmacology
(1995) - et al.
The cloned human 5-HT1E receptor couples to inhibition and activation of adenylyl cyclase via two distinct pathways in transfected BS-C-1 cells
Neuropharmacology
(1994) - et al.
Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene
J Biol Chem
(1990) - et al.
Constitutive Gi2-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists
J Biol Chem
(1999) - et al.
5-HT induces cAMP production in crypt colonocytes at a 5-HT4 receptor
J Surg Res
(1998) - et al.
Isolation of a mouse “5HT1E-like” serotonin receptor expressed predominantly in hippocampus
J Biol Chem
(1992) - et al.
Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD)
Neuropsychopharmacology
(1999) - et al.
Deletion of the serotonin 5-HT2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses
J Biol Chem
(2000) - et al.
Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor
J Biol Chem
(1998) - et al.
Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase
J Biol Chem
(1993)