5 HT7 receptor

Function

When the 5-HT₇ receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein G_s from the GPCR complex. G_s in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT₇ receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. The highest 5-HT₇ receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT₇ receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.

Variants

Three splice variants have been identified in humans (designated h5-HT_7(a), h5-HT_7(b), and h5-HT_7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT_7(a) is the full length receptor (445 amino acids), while the h5-HT_7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT_7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT_7(a). A 5-HT_7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT_7(d), as the rat 5-HT₇ gene lacks the exon necessary to encode this isoform. Drug binding affinities are similar across the three human splice variants; however, inverse agonist efficacies appear to differ between the splice variants.

Discovery

In 1983, evidence for a 5-HT₁-like receptor was first found. Ten years later, 5-HT₇ receptor was cloned and characterized. It has since become clear that the receptor described in 1983 is 5-HT₇.

Clinical significance

This receptor gene is a candidate locus for involvement in autistic disorder and other neuropsychiatric disorders.

Ligands

Numerous ligands bind to the 5-HT₇ receptor with moderate to high affinity.

Agonists

Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT₇ receptor (↑cAMP).

Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no intrinsic activity but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT₇ receptor: ↓cAMP). Neutral antagonists and inverse agonists are typically referred to collectively as "antagonists" and, in the case of the 5-HT₇ receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT_7(a) and h5-HT_7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT_7(b) splice variant.

Inactivating antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitization. Inactivation of the 5-HT₇ receptor, however, does not arise from the classically described mechanisms of receptor desensitization via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization. Inactivating antagonists all likely interact with the 5-HT₇ receptor in an irreversible/pseudo-irreversible manner, as is the case with [³H]risperidone.