5-HT receptor

The 5-HT1B receptor as an example of a metabotropic serotonin receptor. Its crystallographic structure in ribbon representation

The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems.[1][2] They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.[3]

Serotonin receptors are found in almost all animals and humans and are even known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.[4][5]

Classification

With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other serotonin receptors are G protein-coupled receptors that activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. In 2014 a novel 5-HT receptor was described that was isolated from the small white butterfly, Pieris rapae, and named pr5-HT8. It shares relatively low similarity to the known 5-HT receptor classes and does not occur in mammals.[6]

Families

Family Type Mechanism Potential
5-HT1 Gi/Go-protein coupled. Decreasing cellular levels of cAMP. Inhibitory
5-HT2 Gq/G11-protein coupled. Increasing cellular levels of IP3 and DAG. Excitatory
5-HT3 Ligand-gated Na+ and K+ cation channel. Depolarizing plasma membrane. Excitatory
5-HT4 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory
5-HT5 Gi/Go-protein coupled.[7] Decreasing cellular levels of cAMP. Inhibitory
5-HT6 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory
5-HT7 Gs-protein coupled. Increasing cellular levels of cAMP. Excitatory

Subtypes

The 7 general serotonin receptor classes include a total of 14 known serotonin receptors.[8] The specific types have been characterized as follows:[9][10][11]

Overview of Serotonin Receptors
Receptor First cloned Gene(s) Distribution Function Agonists Antagonists Uses of drugs that act on this receptor
Blood vessels CNS GI Tract Platelets PNS Smooth Muscle
5-HT1A 1987 Yes Yes No No No No

Selective (for 5-HT1A over other 5-HT receptors)

Nonselective

5-HT1B 1992 Yes Yes No No No No
5-HT1D 1991 Yes Yes No No No No
5-HT1E 1992 Yes Yes No No No No
  • None known
5-HT1F 1993 No Yes No No No No
  • Migraine
  • None known
5-HT2A 1988 Yes Yes Yes Yes Yes Yes
  • Addiction (potentially modulating) [47]
  • Anxiety[48]
  • Appetite
  • Cognition
  • Imagination
  • Learning
  • Memory
  • Mood
  • Perception
  • Sexual Behavior[49]
  • Sleep[50]
  • Thermoregulation[51]
  • Vasoconstriction[52]
5-HT2B 1992 Yes Yes Yes Yes Yes Yes
5-HT2C 1988 Yes Yes Yes Yes Yes Yes
5-HT3 1993 No Yes Yes No Yes No
  • Addiction
  • Anxiety
  • Emesis
  • GI Motility[69]
  • Learning[70]
  • Memory[70]
  • Nausea
5-HT4 1995 No Yes Yes No Yes No
5-HT5A 1994 No Yes No No No No
  • None thus far
5-HT5B 1993 No No No No No No

Functions in rodents,
pseudogene in humans
  • None thus far
5-HT6 1993 No Yes No No No No
5-HT7 1993 Yes Yes Yes No No No

Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor.

Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine), which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.[35] LSD (a psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist.[35]

References

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  2. ↑ Frazer A, Hensler JG (1999). "Chapter 13: Serotonin Receptors". In Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Philadelphia: Lippincott-Raven. pp. 263–292. ISBN 0-397-51820-X. Retrieved 2008-04-11.
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  6. ↑ Qi YX, Xia RY, Wu YS, Stanley D, Huang J, Ye GY (2014). "Larvae of the small white butterfly, Pieris rapae, express a novel serotonin receptor". J. Neurochem. 131: 767–77. doi:10.1111/jnc.12940. PMID 25187179.
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