5-Hydroxytryptamine 6 receptor (IPR002232)
Short name: 5HT6_rcpt
Overlapping homologous superfamilies
- G protein-coupled receptor, rhodopsin-like (IPR000276)
- 5-Hydroxytryptamine 6 receptor (IPR002232)
5-hydroxytryptamine (5-HT) or serotonin, is a neurotransmitter that it is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS). It is implicated in a vast array of physiological and pathophysiological pathways. Receptors for 5-HT mediate both excitatory and inhibitory neurotransmission, and modulate the release of many neurotransmitters including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin and cortisol. In the CNS, 5-HT receptors can influence various neurological processes, such as aggression, anxiety and appetite and, as a, result are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics and anorectics [PMID: 18476671].
The 5-HT receptors are grouped into a number of distinct subtypes, classified according to their antagonist susceptibilities and their affinities for 5-HT. With the exception of the 5-HT3 receptor, which is a ligand-gated ion channel [PMID: 11989819], all 5-HT receptors are members of the rhodopsin-like G protein-coupled receptor family [PMID: 18476671], and they activate an intracellular second messenger cascade to produce their responses.
5-HT6 receptors are positively coupled to adenylyl cyclase. They are expressed almost exclusively in the brain [PMID: 14965245] and prominently expressed in the caudate nucleus [PMID: 8389146, PMID: 8522988, PMID: 9037500]. Based on their abundance in extrapyramidal, limbic and cortical regions of the brain, it has been suggested that the 5-HT6 receptors play a role in functions like motor control, emotionality, cognition and memory [PMID: 14965245, PMID: 9037500, PMID: 10432491]. Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas [PMID: 10780993, PMID: 11682249, PMID: 1522329], whereas activation enhances GABAergic signaling in a widespread manner [PMID: 17625499]. Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex [PMID: 18625457, PMID: 14618683], while stimulation has the opposite effect [PMID: 17625499].
5-HT6 receptors have high affinity for several typical and atypical antipsychotic agents, including clozapine, olanzapine fluperlapine and seroquel [PMID: 8522988, PMID: 7908055]. This attribute has led to speculation of potential involvement of the 5-HT6 receptor in the pathogenesis of psychiatric disorders. 5-HT6 receptor antagonists have been demonstrated to be active in rodent models of depression, anxiety and obsessive-compulsive disorder, and such agents may be useful treatments for these conditions [PMID: 17625499, PMID: 20217056]. There is also some evidence of enhanced retention of spatial learning following treatment with such compounds [PMID: 11489457, PMID: 11163639]. However, it should be noted that the rodent brain has a notably different regional pattern of 5-HT6 receptor expression in comparison to humans, and little data has been generated in actual clinical populations.
- cd15054 (7tmA_5-HT6)