Serotonin (5-hydroxytryptamine or 5-HT) is synthesized in the central nervous system and in the periphery [1] and mediates its physiological functions by activating serotonin receptors. Among them the 5-HT7 receptor (5-HT7R) is the last serotonin receptor subtype to be discovered in 1993 [2-4]. While highly expressed in two compartments including the CNS [5] and the gastrointestinal tract [6], the 5-HT7R is also found in immune cells [7] and cardiovascular tissues. As such, the 5-HT7R regulates important pathophysiological processes and is poised as a promising target in the treatment of CNS disorders such as sleep disorders, migraine, neuropathic pain or neuro-psychiatric disorders [8-10]; inflammatory, immune-mediated disorders; and blood pressure dysregulation [7].
The 5-HT7R belongs to the superfamily of the G proteins coupled receptors (GPCRs) and is coupled to the heterotrimeric G protein Gs. To date, there are four known splicing variants of 5-HT7R that differ in their length at the carboxyl terminus, a domain critical for signal termination and internalization through β-arrestin recruitment [11]. While the receptor isoforms have different tissue distribution, no differences in their biological and pharmacological properties have been observed [11, 12], except for the 5-HT 7(d) receptor isoform which shows different patterns of receptor trafficking [13].