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.
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.
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
The action of 5-HT at the synapse is terminated by its re-uptake across the pre-synaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and co-transport of sodium and chloride ions and 5-HT from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The 5-HT re-uptake transporter is then available to bind another 5-HT molecule for re-uptake.
There are 7 different types of serotonin receptor (5-HT1–5-HT7) and the 5-HT1, 5-HT2 and 5-HT5 receptors are further classified into subtypes. The 5-HT1 receptors are classified into A, B and D subtypes, which are found in the central nervous system and blood in vessels. Coupled to inhibitory G-proteins, the 5-HT1A receptors have an inhibitory effect on neurotransmission when bound by an agonist.
gA 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.
There are 7 different types of serotonin receptor (5-HT1–5-HT7) and the 5-HT1, 5-HT2 and 5-HT5 receptors are classified into further subtypes. 5-HT2 receptors are classified into A, B and C subtypes, which are found in the central and peripheral nervous systems, platelets and smooth muscle. Coupled to stimulatory G-proteins, the 5-HT2 receptors have a stimulatory effect on neurotransmission when bound by an agonist.
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.
The actions of 5-HT are mediated by a range of different 5-HT receptors. The 5-HT receptors are classified into seven main receptor subtypes, 5-HT1–7. Six of the seven subtypes are G-protein-coupled receptors; 5-HT3 is a ligand-gated cation channel. 5-HT1 receptors occur primarily in the brain and cerebral blood vessels (5-HT1D only), where they mediate neural inhibition and vasoconstriction. They function mainly as inhibitory presynaptic receptors, linked to inhibition of adenylate cyclase. Specific agonists at 5-HT1 receptors include sumatriptan (used in migraine therapy) and buspirone (used in the treatment of anxiety). Spiperone and methiothepin are specific antagonists of 5-HT1 receptors. 5-HT2 receptors are found in the CNS and in many peripheral sites. They act through phospholisae C to produce excitatory neuronal and smooth muscle effects. Specific ligands at 5-HT sites include LSD – acting as an agonist in the CNS and as an antagonist in the periphery – and ketanserin and methysergide (both antagonists). 5-HT3 receptors occur mainly in the peripheral nervous system, particularly on nociceptive afferent neurones and on autonomic and enteric neurones. The effects of these receptors are excitatory, mediated by receptor-coupled ion channels. 5-HT3 antagonists (eg ondansetron, tropisetron) are used predominantly as anti-emetic drugs. 5-HT4 receptors are found in the brain, as well as peripheral organs like the heart, bladder and gastrointestinal (GI) tract. Within the GI tract they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis. A specific 5-HT4 agonist is metoclopramide used for treating gastrointestinal disorders. Little is known about the function and pharmacology of 5-HT5, 5-HT6 and 5-HT7 receptors.
5-HT receptors are found in the peripheral nervous system (PNS) as well as in the CNS. They are linked to phospholipase C, and thus stimulate IP3 formation, and exert an excitatory post-synaptic effect. The 5-HT2A subtype is functionally the most important and these receptors are abundant in the brain, particularly the cortex and hippocampus. The effects of 5-HT on smooth muscle and platelets are mediated by 5-HT2A. Some of the behavioural effects of agents such as lysergic acid diethylamide – acting as an agonist in the CNS and as an antagonist in the periphery – are also mediated at 5-HT2A receptors. Specific antagonists at these sites include ketanserin, cyproheptadine and methysergide, which is used primarily for migraine prophylaxis. The 5-HT2B and 5-HT2C subtypes have a much more limited distribution and functional role than the 5-HT2A receptors. The role of 5-HT2 receptors in normal physiological processes is a minor one, but becomes more prominent in pathological conditions, such as asthma and vascular thrombosis.
To date seven main types of 5-HT receptor have been identified in the brain. Two 5-HT5 receptor subtypes (5-HT5A, 5-HT5B) have also been recognised. The main sites of 5-HT5A mRNA expression are the cerebral cortex, hippocampus, hypothalamic area, amygdala and cerebellum. However, the physiological role of this receptor in normal brain function is still unknown. The human 5-HT5B gene does not encode a functional protein because its coding sequence is interrupted by stop codons.