The 5-HT2C receptor was identified as a high-affinity [3H]5-HT-binding site in epithelial cells of the choroid plexus (Berg et al. 2008; Heisler et al. 1998; Miller 2005). Originally, it was classified as a member of the 5-HTj receptor family and was named the 5-HT1C receptor (Pazos et al. 1985). Later, this receptor was reclassified as 5-HT2C due to its structural and signaling similarities with the 5-HT2 receptor subclass (Hoyer et al. 1994). The partial cloning of the mouse 5-HT2C receptor (Lubbert et al.

1987) was followed by the sequencing of the full-length clone in the rat (Julius et al.

1988), human (Saltzman et al. 1991), and mouse (Foguet et al. 1992). Comparison of the cDNA-deduced amino acid sequences from rat, mouse, and human reveals strong sequence homology. The gene for the 5-HT2C receptor is located on the human X chromosome at position q24 (Xq24), and on mouse X chromosome at region d-F4 (Milatovich et al. 1992). Mice lacking the 5- HT2C receptor have been produced and show an eating disorder and epilepsy (Tecott et al. 1995). Xie et al. isolated the complete 4775-nt cDNA encoding the human 5-HT2C receptor and characterized its gene structure (Xie et al. 1996). The entire 5-HT2C receptor gene from exon I to exon VI spans at least 230 kb of DNA, encompassing six exons and five introns (Xie et al. 1996). The coding sequence of the human 5-HT2C receptor gene is interrupted by three introns (rather than two as in the case of the 5-HT2A and 5-HT2B receptors) (Stam et al. 1994), and the positions of the intron-exon junctions are conserved between the human and the mouse 5-HT2C receptor genes (Xie et al. 1996).

This complex gene structure allows for the existence of variants of the 5-HT2C receptor. An alternatively spliced variant of the 5-HT2C receptor RNA that contains a 95-nt deletion in the region coding for the second intracellular loop and the fourth

Medical and Research Services of the Ralph H. Johnson Veterans Affairs Medical Center and the Department of Medicine (Nephrology Division), Medical University of South Carolina, 96 Jonathan Lucas Street, MSC 629 Charleston, SC 29425, USA e-mail: [email protected]

G. Di Giovanni et al. (eds.), 5-HT2C Receptors in the Pathophysiology of CNS Disease, The Receptors 22, DOI 10.1007/978-1-60761-941-3_5, © Springer Science + Business Media, LLC 2011

transmembrane domain of the receptor generates a truncated, nonfunctional isoform of the 5-HT2C receptor (Xie et al. 1996; Canton et al. 1996). In addition, the 5-HT2C receptor exhibits a unique mechanism of generating multiple functional receptor variants through a process called mRNA editing (Burns et al. 1997) recently reviewed by Werry et al. (2008a), which will be discussed in Sect. 5.1.1.

The 5-HT2C receptor is expressed primarily in the central nervous system (Roth et al. 1998). High levels of 5-HT2C receptor expression have been detected by ligand autoradiography, immunocytochemistry, and in situ hybridization in the choroid plexus, the cortex, the nucleus accumbens, the amygdala, the hippocampus, caudate nucleus, and substantia nigra (Pazos et al. 1985; Mengod et al. 1990; Abramowski et al. 1995). The highest density of 5-HT2C receptors is found in epithelial cells of the choroid plexus, where these receptors control spinal fluid production (Leysen 2004). Pre- and postsynaptic localizations of 5-HT2C receptors have been confirmed by electron-microscope studies performed in the mouse (Bécamel et al. 2004). 5-HT2C receptors also are present in hypothalamic pro-opiomelanocortin (POMC)/ cocaine amphetamine-regulated transcript (CART) neurons within the arcuate nucleus (Heisler et al. 2002) and in rat retinal neurons (Pérez-León et al. 2004).

With regard to signaling, 5-HT2C receptors are positively coupled via Gaq to phospholipase Cb (PLC) protein in several brain regions including choroid plexus. In addition to PLC, 5-HT2C receptors couple to multiple cellular effector systems including phospholipase A2 (PLA2), phospholipase D (PLD), extracellular signalregulated kinases (ERK1/2), pertussis toxin-sensitive G proteins, PDZ domain-containing proteins, and to regulation of different channels and transport processes (for reviews, see Leysen 2004; Raymond et al. 2001, 2006; Millan et al. 2008). Consequently, the net cellular effect of activation of 5-HT2C receptors results from concurrent regulation of several effector pathways within cells.

Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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