Phospholipase C

Perhaps the best-studied effector system to which the 5-HT2C receptor couples is the phospholipase C6 (PLC) pathway (for reviews, see Roth et al. 1998; Leysen 2004).

Fig. 5.2 G-protein-signaling and non-G-protein-coupling partners of the 5-HT2C receptor. The left panel depicts the three major heterotrimeric G-protein families (G n, Gao/i, and Ga13) through which the 5-HT2C receptor activates phospholipase C (PLC), phospholipase A2 (PLA2), and phos-pholipase D (PLD) and inhibits the accumulation of cyclic adenosine monophosphate (cAMP). Activation of phospholipase C leads to the hydrolysis of PIP2, resulting in the generation of dia-cylglycerol (DAG) and inositol trisphosphate (IP3), which lead to activation of protein kinase C (PKC) and elevation of intracellular calcium levels, respectively. The receptor also modulates many ion channels and transporters, nitric oxide synthase, and other effectors through G proteins (see text for details). The right panel depicts various proteins that physically associate with the 5-HT2C receptor and that might mediate non-G-protein-mediated signals. Beta-arrestin2 (|AR2) binds to both the second intracellular loop and carboxyl terminus of the receptor. In the carboxyl terminus, |AR2 physically associates with the receptor and calmodulin (CaM), resulting in activation of the mitogenic kinase, extracellular signal-regulated kinases (ERK). The third intracellular loop binds to phosphatase and tensin homolog (PTEN), which is a lipid and protein phosphatase. The carboxyl terminus also binds to cytoskeletal elements such as actin, spectrin, and CAPZ and to PTD4 (a putative GTP-binding protein) and PICOT (PKC 9-interacting protein). Through a PDZ-ligand interaction, the carboxyl terminus of the receptor also interacts with PDZ-containing proteins such as MUPP1, PSD95, MPP3, and the Veli-CASK-Mint-Munc18 complex (see text for details). For the most part, the functional effects of those interactions remain to be elucidated

Stimulation of PLC by the 5-HT2C receptor leads to the production of diacylglycerol and inositol triphosphate (IP3) and subsequent intracellular calcium release. This signaling pathway has been demonstrated in several brain regions including choroid plexus and in recombinant cell lines expressing the 5-HT2C receptor (Chang et al. 2000; Conn et al. 1986; Berg et al. 1994). The activation of PLC by endogenously expressed 5-HT2C receptor most likely is mediated through Gaq/11-proteins, although coupling of 5-HT2C receptor to PLC activation through PTX-sensitive Gai/Gao subtypes has been shown in Xenopus laevis oocytes (Chen et al. 1994) and in HEK 293 cells overexpressing 5-HT2C receptors (Alberts et al. 1999). In addition, involvement of botulinum ADP-ribosyltransferase-sensitive low-molecular-weight Gproteins in IP3 accumulation induced by the 5-HT2C receptors transfected into COS-7 cells also has been proposed (Tohda et al. 1995).

RNA-edited isoforms of the 5-HT2C receptor, 5-HT2C-VGV, and 5-HT2C-VSV, which have different amino acids in the second intracellular loop from the nonedited 5-HT2C-ini receptor, have reduced capacity to activate PLC signaling pathway compared with the nonedited receptor (Burns et al. 1997; Fitzgerald et al. 1999; Niswender et al. 1999; Berg et al. 2001).

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How To Have Beutiful Non Aging Skin

Age does a lot of things to us and most of them arent good. Sure, we may get wiser, and more knowledgeable as a result of our experiences over time, but time also takes a hefty toll on our health, and appearance.

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