Cl Channels

The 5-HT2C receptor also has been shown to stimulate an apical Cl- conductance in mouse choroid plexus (Hung et al. 1993). 5-HT2C receptors expressed in

Xenopus laevis oocytes can stimulate Ca2+ release from IP3-sensitive intracellular stores, which results in the opening of Ca2+-gated Cl- channels (DiMagno et al. 1996). This effect occurs through endogenous Gao proteins. The same Cl- current could be also stimulated by coexpression of 5-HT2C receptors with PTX-sensitive (Gao) and PTX-insensitive (G ) G protein subunits, suggesting that 5-HT2C receptor couples within the same cell type to several different heterologously expressed G protein a subunits to activate endogenous Xenopus laevis oocyte Ca2+-gated Cl- channels. This effect was mediated by an endogenous PLC-b (Quick et al. 1994).

In addition to 5-HT2C receptor-dependent regulation of K+ and Cl- channels, studies in the prefrontal cortex (PFC) have described effects of serotonin treatment on sodium and Ca2+ currents (Carr et al. 2002; Day et al. 2002), and on N-methyl-D-aspartate (NMDA) receptor channels (Yuen et al. 2008). PFC pyramidal neurons express detectable levels of 5-HT2A and/or 5-HT2C receptor mRNA, with half of the cells expressing both mRNAs. However since 5-HT2A and 5-HT2C receptors have similar pharmacological profiles and intracellular signaling cascades (Sanders-Bush et al. 2003), these studies did not address the relative contribution of the 5-HT2A and 5-HT2C receptors to 5-HT effects. 5-HT2A/C receptor stimulation decreased rapidly inactivating Na+ currents by reducing maximal current amplitude, and by producing a negative shift in the voltage dependence of fast inactivation. These effects of 5-HT on voltage-dependent Na+ channels in PFC pyramidal neurons were mediated by Gaq- dependent activation of PLC and subsequent activation of PKC, and resulted in reduced dendritic excitability (Carr et al. 2002). Voltage-clamp and single-cell RT-PCR studies in acutely isolated deep-layer prefrontal pyramidal neurons show that 5-HT2A/C receptor activation reduces L-type Cav1.2 Ca2+ channel currents via a signaling cascade initiated by Gaq protein stimulation of PLCb, leading to the mobilization of IP3-sensitive intracellular Ca2+ stores and activation of the Ca2+-dependent phosphatase calcineurin (Day et al. 2002). 5-HT2A/C receptor activation regulates N-methyl-D-aspartate (NMDA) receptor currents in PFC pyramidal neurons by opposing the 5-HT1A receptor-induced disruption of microtubule-based transport of NMDA receptors (Yuen et al. 2008).

Furthermore 5-HT2C receptors have been shown to inhibit g-aminobutyric acid (GABA)-A receptor channels by a Ca2+-dependent, phosphorylation-independent mechanism in Xenopus oocytes (Huidobro-Toro et al. 1996). Activation of the 5-HT2C receptor in hypothalamic pro-opiomelanocortin (POMC) neurons desensitizes the GABAB response in neurons through inhibition of G-protein-coupled inwardly rectifying potassium (GIRK) channels. The mechanism involves activation of PLC by Ga subunits and hydrolysis of plasma membrane PIP2 to IP3 and DAG, which leads to the IP3-induced release of Ca2+ from intracellular stores and DAG-dependent activation of PKC. Next, PKC phosphorylates and up-regulates adenylyl cyclase VII activity, leading to cAMP-dependent activation of PKA, which can rapidly uncouple GABAB from effector system through phosphorylation of GIRK (Qiu et al. 2007).

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