Human HTR2A

5-Hydroxytryptamine receptors

5-HT receptors are, with the exception of the ionotropic 5-HT₃ class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing... [read more] that produces isoforms of the 5-HT_2A (non-functional), 5-HT_2C (non-functional), 5-HT₄, 5-HT₆ (non-functional) and 5-HT₇ receptors. Unique amongst the GPCRs, RNA editing produces 5-HT_2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to G_q/11 and also pharmacology [1,2]. Most 5-HT receptors (except 5-ht_1e and 5-ht_5b) play specific roles mediating functional responses in different tissues (reviewed by [3,4]).

References

1. Bockaert J, Claeysen S, Bécamel C, et al. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 2006;326:553-72.
2. Werry TD, Loiacono R, Sexton PM, et al. RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther 2008;119:7-23.
3. Villalón CM, Centurión D. Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications. Naunyn Schmiedebergs Arch Pharmacol 2007;376:45-63.
4. Ramage AG, Villalón CM. 5-hydroxytryptamine and cardiovascular regulation. Trends Pharmacol Sci 2008;29:472-81.

5-HT2 receptors

The 5-HT₂ family comprise three receptors; 5-HT_2A, 5-HT_2B and 5-HT_2C that exhibit 42-51% overall amino acid sequence identity and can couple to G_q/G₁₁ to increase the hydrolysis of inositol phosphates and elevate cytosolic [Ca²⁺]. In addition, G_q/G₁₁ coupling to other transduction pathways is apparent (e.g. PI3K/Akt and ERK). The 5-HT_2C receptor is prone to RNA editing, resulting in multiple distinct isoforms that may display altered transduction efficiency as well as preferred transduction pathway coupling. This RNA editing can be regulated by psychotropic drugs, thereby altering the functionality of these receptors in a region-specific manner in brain. These receptors demonstrate several intriguing and subtle pharmacological properties that have been studied in depth. 5-HT₂ receptors display agonist-directed signaling or “biased agonism” in which the same agonist in different cell types or different agonists in the same cell type will differentially activate multiple, distinct signaling pathways.

Preliminary evidence indicates that 5-HT_2B receptors can act as autoreceptors in serotonin neurons; these receptors have also been found to interact reciprocally with tyrosine kinase receptors to induce mitogenic effects at very low concentrations of 5-HT. There are several examples of 5-HT₂ receptors dimerizing both to like and dissimilar receptors. An intriguing reciprocal interaction occurs between 5-HT_2A and mGluR₂ glutamate receptors in cerebral cortex, whereby activation of the glutamate receptor inhibits the function of 5-HT_2A receptors only when activated by hallucinogenic (such as LSD) but not non-hallucinogenic 5-HT_2A receptor agonists (such as lisuride).

Pharmacology

Selective antagonists for each of the 5-HT₂receptors are available (e.g. volinanserin [5-HT_2A receptor], RS 127445 [5-HT_2B receptor], SB 242084 [5-HT_2C receptor]), whereas selective agonists are limited (e.g. lorcaserin is an agonist at 5-HT_2C receptors although displays only ~15-fold selectivity over the 5-HT_2A receptor).

Clinical significance

These receptors have a complex and interesting role in psychotropic pharmacology. Some hallucinogens display “biased agonism” at 5-HT_2A receptors. A number of atypical antipsychotics are 5-HT_2A/C antagonists or inverse agonists (e.g. asenapine, chlorpromazine, pimozide, clozapine, risperidone), which may contribute to the efficacy of these drugs, many of which display wide ranging poly-pharmacology. Transgenic and pharmacological data suggest that increased appetite and metabolic syndrome may be associated with 5-HT_2C receptor blockade. In addition, non-selective 5-HT receptor antagonists such as methysergide are used in the prophylactic treatment of migraine. Activation of 5-HT_2B receptors in heart may lead to cardiac valvulopathy; this may be a risk for both non-selective 5-HT releasers (e.g. fenfluramine; which led to withdrawal from the clinic) or selective 5-HT_2B receptor agonists. [close]