5-HT Receptors

There are seven 5-HT (serotonin) receptor subtypes. This collection of receptors is substantially larger than other neurotransmitter receptor families. The receptors vary in structure (G-protein coupled, ligand gated ion channel) and anatomical distribution, although there is significant overlap among the subtypes. There are also differences in cellular distribution with receptors located post-synaptically, as well as pre-synaptically and on other cell structures (e.g., somatodendritic). The subtypes have varying effects on second messenger systems such as adenylyl cyclase and phospholipase C.

5-HT1 Receptors

ü Consists of the following subtypes: 5-HT1A, 5-HT1B (rat, mouse, hamster only), 5-HT1D (humans, guinea pig, calf, dog only), 5-HT1E, 5-HT1F

ü Type: G protein coupled (G_i , 7 transmembrane spanning protein)

ü Second messenger coupling: Negatively coupled to adenylyl cyclase

5-HT1A Receptors

• Neuronal location: postsynaptic (forebrain regions), presynaptic (mesencephalic and medullary raphe nuceli)
• Distribution: high density in limbic areas, particularly the hippocampus, lateral septum, cortical areas (notably cingulate and entorhinal cortices), mesencephalic raphe nuceli.

5-HT1B Receptors

• Neuronal location: postsynaptic, presynaptic (nerve terminals of 5-HT and non-5HT neurons)
• Distribution: basal ganglia (particularly the globus pallidus, substantia nigra, ventral pallidum and entopeduncular nucleus), hippocampus (subiculum)

5-HT1D Receptors

• Neuronal location: presynaptic (nerve terminals of 5-HT and non-5HT neurons)
• Distribution: difficult to determine as levels appear to be low and there is no radioligand that is able to discriminate this receptor from the 5-HT1B receptor. In humans, receptor appears to be present in the basal ganglia (globus pallidus and substantia nigra), specific midbrain areas and spinal cord.

5-HT1E Receptors

• Neuronal location: postsynaptic
• Distribution: there are no selective radioligands for this receptor but studies examining the binding of ligands to non-5-HT1A/1B1D/2C sites suggest that high levels of these sites are present in the caudate putamen, cortex and claustrum with detectable levels in the hippocampus and amygdala.

5-HT1F Receptors

• Neuronal location: postsynaptic (?)
• Distribution: Using the novel 5-HT1F radioligand [³H]-LY334370, 5-HT1F receptors are predicted to be present in the cortex, hippocampus and certain areas of the basal ganglia (discrete localization but low abundance)

5-HT2 Receptors

ü Consists of following subtypes: 5-HT2A, 5-HT2B, 5-HT2C

ü Type: G protein coupled (Gq, 7 transmembrane spanning protein)

ü Second messenger system: Positively coupled to Phospholipase C

5-HT2A Receptors

• Neuronal location: postsynaptic; nerve terminal of non-5-HT neurons.
• Distribution: high density in cortical areas (neocortex, entorhinal and pyriform cortex, claustrum), nucleus accumbens, olfactory tubercle, caudate nucleus

5-HT2B receptors

• Neuronal location: ?
• Distribution: measurement of 5-HT2B mRNA and 5-HT2B receptor-like immunoreactivity indicate a discrete localization: cerebellum, lateral septum, dorsal hypothalamus and medial amygdala.

5-HT2C receptors:

• Neuronal location: postsynaptic, nerve terminals of non-5-HT neurons.
• Distribution: high density in choroid plexus, cortex (cingulate, pyriform, retrosplenial and olfactory nucleus), limbic system (amygdala, hippocampus, nucleus accumbens) and basal ganglia (caudate, substantia nigra).

5-HT3 Receptors

ü Consists of 2 subunits (A and B)

ü Type: Ligand gated ion channel (equal permeability to sodium and potassium)

ü Neuronal location: postsynaptic; nerve terminals of non-5-HT neurons

ü Distribution: high levels in dorsal vagal complex; low levels in hippocampus, amygdala and superficial layers of cerebral cortex.

5-HT4 Receptors

ü Consists of 4 variants: 5-HT4S, 5-HT4L, 5-HT4C, 5-HT4D

ü Type: G protein coupled (G_i , 7 transmembrane spanning protein)

ü Second messenger coupling: Negatively coupled to adenylyl cyclase

ü Neuronal location: postsynaptic; nerve terminals of non-5-HT neurons

ü Distribution: High density in nigrostriatal and mesolimbic areas

5-HT5 Receptors

ü Consists of following subtypes: 5-HT5A and 5-HT5B

ü Type: G protein coupled (?), G_o, G_x

ü Second messenger coupling: 5-HT5A - negatively coupled to adenylyl cyclase in HEK293 cells. 5-HT5B: ?

ü Neuronal location: ?

ü Distribution:

§ 5-HT5A mRNA present in hypothalamus, hippocampus, cerebral cortex, thalamus, pons, striatum and medulla.

§ 5-HT5B - in situ hybridization data suggests that 5-HT5B receptors are present in the supraoptic nucleus of the hypothalamus, hippocampus, lateral habenula, olfactory bulb, entorhinal and pyriform cortices, dorsal raphe nucleus.

5-HT6 Receptors

• Type: G protein coupled (G_i, 7 transmembrane spanning protein)
• Second messenger coupling: Negatively coupled to adenylyl cyclase
• Neuronal location: postsynaptic
• Distribution: measurement of 5-HT6 receptor mRNA and 5-HT6 receptor-like immunoreactivity indicate that 5-HT6 receptors are present in the striatum, hippocampus, nucleus accumbens and olfactory tubercle.

5-HT7 Receptors

• Type: G protein coupled (Gi, 7 transmembrane spanning protein)
• Second messenger coupling: Negatively coupled to adenylyl cyclase
• Neuronal location - postsynaptic (?)
• Distribution: high density in thalamus, hypothalamus and hippocampus; lower levels in cerebral cortex and amygdala
• 4 splice variants of this receptor: 5-HT7A, 5-HT7B, 5-HT7C and 5-HT7D (to date, no major differences in the pharmacology between the variants has been reported)

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Dr. Charles Ashby contributed substantially to the content of this page

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