Regulation of TRPVi responsiveness to anandamide

In general, the in vivo activity of TRPV1 appears to be dependent on its sensitization state. There are numerous mechanisms identified which regulate TRPV1 activity. One of the most studied pathways is the phosphorylation ofTRPVl, which affects its sensitivity to vanilliods and to anandamide (Fig. 15.2). TRPV1 is phosphorylated on serine and threonine residues by protein kinase C (PKC) (Bhave et al., 2003; Premkumar and Ahern, 2000); PKA (Bhave et al., 2002), protein kinase D (Wang et al., 2004), and calcium-calmodulin dependent protein kinase II (Jung et al., 2004). Protein phos-phatase 2B (calcineurin) was found to be important for dephosphorylation, leading to receptor desensitization (Cortright and Szallasi, 2004; Docherty et al., 1996; Lizanecz et al., 2006; Mohapatra and Nau, 2005). In addition, phosphorylation ofTRPVl on tyrosine has also been reported (Jin et al., 2004). A further regulatory mechanism for TRPV1 is through interaction with phosphatidylinositol-4,5-bisphosphate (Chuang et al., 2001; Lukacs et al., 2007). Finally, other lipids may also regulate TRPV1 (De Petrocellis et al., 2001b, 2004; Smart et al., 2002; Vandevoorde et al., 2003).

Activation of PKC was found to sensitize TRPV1 to anandamide (Bhave et al., 2003; Premkumar and Ahern, 2000), probably through phosphorylation of serines 502 and 800 (Bhave et al., 2003) leading to increased gating probability of the channel (Vellani

Protein kinases (PKA, PKC, PKD, CaMKII)

Protein phosphatase 2B

Protein phosphatase 2B

Figure 15.2 Sensitization of TRPV1 to anandamide. The vanilloid receptor 1 (TRPV1) may be phosphorylated by various kinases (e.g., by protein kinase C, PKC; by protein kinase A, PKA; and by calcium-calmodulin dependent protein kinase II, CaMKII) on critical serine/threonine residues. These phosphorylations sensitize TRPV1 to anandamide, resulting in an apparent increase in the efficacy of anandamide and other vanilloids on TRPV1. In contrast, phosphorylated TRPV1 may be depho-sphorylated by the Ca2+-dependent protein phosphatase 2B (calcineurin), resulting in decreased sensitivity and efficacy.

Figure 15.2 Sensitization of TRPV1 to anandamide. The vanilloid receptor 1 (TRPV1) may be phosphorylated by various kinases (e.g., by protein kinase C, PKC; by protein kinase A, PKA; and by calcium-calmodulin dependent protein kinase II, CaMKII) on critical serine/threonine residues. These phosphorylations sensitize TRPV1 to anandamide, resulting in an apparent increase in the efficacy of anandamide and other vanilloids on TRPV1. In contrast, phosphorylated TRPV1 may be depho-sphorylated by the Ca2+-dependent protein phosphatase 2B (calcineurin), resulting in decreased sensitivity and efficacy.

The potentiation of anandamide effects caused by PKC activation was accompanied by a significant increase in CGRP release induced by anandamide (Orliac et al., 2007). PKA also sensitizes TRPV1 to anandamide, probably through the phosphorylation of serine 116 (Bhave et al., 2002). A decisive role of PKC and protein phosphatase 2B (calcineurin) was found in the regulation of anandamide responsiveness of TRPV1 (Lizanecz et al., 2006). These latter findings have suggested the following model. According to this model, TRPV1 is phosphorylated under resting conditions. Upon activation by anandamide, Ca2+ flows through the channel and activates the Ca2+-depen-dent protein phosphatase 2B. The activated phosphatase then dephosphory-lates the TRPV1, making it insensitive to anandamide and other vanilloids (acute desensitization) (Lizanecz et al., 2006). Closure of the channel may result in restored (low) intracellular Ca2+ concentrations, inactivation of protein phosphatase 2B, and in the subsequent phosphorylation of TRPV1.

An additional regulatory pathway was suggested in the case ofinflamma-tion. Pretreatment with CCL3 (a proinflammatory chemokine) enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and PKC, respectively (Zhang et al., 2005).

The first lipid with an "entourage" effect on TRPV1 was the palmitoy-lethanolamide, which enhanced the effect of anandamide (De Petrocellis et al., 2001b). N-morpholino- and N-diethyl-analogs of palmitoylethano-lamide also increased the sensitivity ofTRPV1 to activation by anandamide without affecting fatty acid amidohydrolase activity (Vandevoorde et al., 2003). In addition, N-palmitoyl- and N-stearoyl-dopamine may also play an "entourage" role (De Petrocellis et al., 2004).

In conclusion, the host cell expression system modulates the regulation of TRPV1 receptor activity and suggests that anandamide activation of native human TRPV1 receptors in vivo is dependent on cell-specific regulatory factors/pathways (Bianchi et al., 2006). Because TRPV1 is now thought to be present in numerous cell types other than sensory neurons and these various cell types will have different levels ofexpression ofdifferent regulatory factors for TRPV1, the clear expectation is that TRPV1 behavior and pharmacology will be different in these different contexts.

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