Recent research interest has turned to the role of endocannabinoids as retrograde neurotransmitters in synaptic modulations. Among five identified endocannabinoids, AEA, the amide between arachidonic acid (AA) and ethanolamine, was the first endocannabinoid named as an endogenous ligand for cannabinoid (CB) receptors. Unlike classical neurotransmitters, the endo-cannabinoids can travel backward to presynaptic neurons after released from the postsynaptic neurons upon depolarization. The endocannabinoids bind to and activate the presynaptic CB1 receptors (Pacher et al., 2006; Wilson and Nicoll, 2001). Activation of the CB1 receptors in turn inhibits neurotransmitter release by inducing hyperpolarization and/or shutting voltage sensitive calcium channels. This retrograde endocannabinoid signaling plays an essential role in synaptic plasticity. On the other hand, accumulating evidence has emerged to show that some pharmacological effects produced by endogenous and exogenous CB receptor ligands are not mediated by CB1 or CB2 receptors (Oz, 2006; van der Stelt and Di Marzo, 2005). For instance, AEA and fatty acids have been found to modulate the functional properties of K+, Na+, and Ca2+ channels in a CB receptor-independent manner. AEA has also been shown to activate the vanilloid type 1 transient receptor potential channel
(TRPV1) in native neurons and in recombinant cell lines expressing TRPV1 channels (van der Stelt and Di Marzo, 2005). Because the cell lines such as HEK-293 cells and Xenopus oocytes that are used to express TRPV1 channels do not contain any of known CB receptors, the action of AEA on TRPV1 is thought to be a direct effect or (CB) receptor-independent effect. The receptor-independent effects of endocannabinoids on voltage-gated ion channels and TRPV1 channels were reviewed extensively (Oz, 2006). This chapter is intent to focus on the receptor-independent effects of fatty acids, endocan-nabinoids, and cannabimimetic lipids on the Cys-loop ligand-gated ion channels (LGICs).
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