The serotonin-6 receptor as a novel therapeutic target

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT(1), 5-HT(2), 5-HT(3), 5-HT(4), 5-HT(5), 5-HT(6), and 5-HT(7) receptors. Among them, the 5-HT(6) receptor (5-HT(6)R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT(6)R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT(6)R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT(6)R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT(6)R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety.

Keywords: Alzheimer; Fyn; Jab1; ST1936; cognitive disorders; depression.

Fig. 1

5-HT₆R-mediated signal transduction pathways. The activation of 5-HT₆R increases DARPP-32 activities by PKA [64] and ERK1/2 activities via Fyn- and PKA-dependent pathways [32]. Fyn also leads to the surface expression of 5-HT₆R via a direct interaction between Fyn and the carboxyl terminus of 5-HT₆Rs [32]. In addition, a novel interaction between human HT₆R (iL3 and the carboxyl terminus) and Jab1 was demonstrated by Yun et al. [68]. The expression of Jab1 mediates the modulation of the membrane expression and activity of 5-HT₆Rs. 5-HT₆Rs also affect the cytosol/nuclear distribution of Jab1 as well as the interaction between Jab1 and c-Jun, a target protein downstream of Jab1.