Get to know serotonin receptors

There are four broad ‘superfamilies’ of receptor: (1) the channel-linked (ionotropic) receptors; (2) the G-protein coupled (metabotropic) receptors; (3) the kinase-linked receptors; and (4) receptors that regulate gene transcription. The 5-HT1, 2, 4, 5, 6 and 7 receptors belong to the G-protein coupled superfamily. They are membrane receptors that have 7 transmembrane spanning a-helices. 5-HT binding to the ‘binding groove’ on the extracellular portion of the receptor activates the G-proteins, which initiate secondary messenger signalling pathways. The downstream effect is either inhibitory or stimulatory, depending on the type of G-protein linked to the receptor – 5-HT1 receptors are linked to inhibitory G-proteins, whereas 5-HT2, 4, 6 and 7 are linked to stimulatory G-proteins.

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References

Histamine, serotonin and the ergot alkaloids. In: Basic and clinical pharmacology, 8^th edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:265–291

How drugs act: molecular aspects. In: Pharmacology, 4^th edition. Rang HP, Dale MM and Ritter JM. Edinburgh, UK: Harcourt Publishers Ltd, 2001:19–46.

The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand-gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of 5 subunits. Two subunits have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterised

Binding of an agonist at the 5-HT binding site causes a conformational change and activation of the 5-HT3 receptor. As a ligand gated ion channel this permits the movement of positively charged ions from the synaptic cleft into the cytoplasm. Binding of an antagonist at the 5-HT binding site prevents this activation and cell depolarisation is inhibited.

A 5-HT1A receptor antagonist prevents the activation of the 5-HT1A receptor. The 5-HT1A receptor is coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding, and inhibit secondary messenger signaling mechanisms. Antagonist binding inhibits this usual process, resulting in cell depolarisation.

Binding of a partial agonist to the 5-HT1A receptor causes the dissociation of inhibitory G-proteins. The G-protein alpha sub-unit binds to and inhibits adenylate cyclase. This prevents the conversion of ATP to cAMP and the initiation of other secondary messenger signaling mechanisms, hence cell depolarisation is inhibited.

A 5-HT2 receptor antagonist prevents the activation of the 5-HT2 receptor. The 5-HT2 receptor is coupled to stimulatory G-proteins, which dissociate from the receptor on agonist binding, and initiate secondary messenger signaling mechanisms. This causes cell depolarisation, which is inhibited by antagonist binding.

G-protein coupled receptors

Before I explain serotonin receptors family I want to go over in deep detail about G-protein coupled receptors, and we will examine closely about specific serotonin subtypes and their functions., This will give us insight of how atypical antipsychotics work and clues of how these agents cause side effects. I have a nice illustration and description to show you below.

Robert T. Dorsam and J. Silvio Gutkind, G-protein-coupled receptors and cancer, Nature Reviews Cancer 7, 79-94 (February 2007)

Various ligands use G-protein-coupled receptors (GPCRs) to stimulate membrane, cytoplasmic and nuclear targets. GPCRs interact with heterotrimeric G proteins composed of , and subunits that are GDP bound in the resting state. Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of GDP from the subunit followed by GTP-binding to G and the dissociation of G from G subunits.

The subunits of G proteins are divided into four subfamilies: G_s, G_i, G_q and G₁₂, and a single GPCR can couple to either one or more families of G proteins. Each G protein activates several downstream effectors. Typically G_s stimulates adenylyl cyclase and increases levels of cyclic AMP (cAMP), whereas G_i inhibits adenylyl cyclase and lowers cAMP levels, and members of the G_q family bind to and activate phospholipase C (PLC), which cleaves phosphatidylinositol bisphosphate (PIP₂) into diacylglycerol and inositol triphosphate (IP₃).

The G subunits and G subunits function as a dimer to activate many signalling molecules, including phospholipases, ion channels and lipid kinases.

Besides the regulation of these classical second-messenger generating systems, G subunits and G subunits such as G₁₂ and G_q can also control the activity of key intracellular signal-transducing molecules, including small GTP-binding proteins of the Ras and Rho families and members of the mitogen-activated protein kinase (MAPK) family of serine-threonine kinases, including extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 and ERK5, through an intricate network of signalling events that has yet to be fully elucidated. Ultimately, the integration of the functional activity of the G-protein-regulated signalling networks control many cellular functions, and the aberrant activity of G proteins and their downstream target molecules can contribute to cancer progression and metastasis.

5-HT, 5-hydroxytryptamine; ECM, extracellular matrix; GABA, gamma-aminobutyric acid; GEF, guanine nucleotide exchange factor; GRK, G protein receptor kinase; LPA, lysophosphatidic acid; PI3K, phophatidylinositol 3-kninase; PKA and PKC, protein kinase A and C; S1P sphingosine-1-phosphate.