The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase
The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase
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DOI：
10.1046/j.1471-4159.2001.00406.x
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发表时间：
2001-06-01
影响因子：
4.7
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
--
作者：
De Petrocellis, L;Harrison, S;Di Marzo, V
内源性大麻素受体配体，大麻素酰胺（AEA），是辣椒素的香草素受体1型（VR 1）的完全激动剂。在这里;我们证明，蛋白激酶A（PKA）的同时激活可显著增加AEA对VR 1受体的效力和功效。在过表达人VR 1的人胚肾（HEK）细胞中，AEA诱导由该受体介导的胞质Ca 2+浓度升高。在存在毛喉素（FRSK，1-5 μ M）或cAMP类似物8-Br-cAMP（10-100 μ M）的情况下，该效应的EC 50降低5倍。选择性PKA抑制剂可阻断8-Br-cAMP和FRSK的作用。FRSK（10 nM）也有效地增强了感觉神经元和VR 1介导的收缩AEA的离体豚鼠支气管，这种效果被废除PKA抑制剂。在大鼠背根神经节切片中，FRSK（10 nM）可将AEA诱导的P物质释放（VR 1激活介导的效应）增强3倍。因此，AEA刺激感觉VR 1的能力，以及随后的神经肽释放，似乎受到PKA激活状态的调节。这一观察结果支持了内源性AEA可能在某些病理生理条件下刺激VR 1的假设。
The endogenous cannabinoid receptor ligand, anandamide (AEA), is a full agonist of the vanilloid receptor type 1 (VR1) for capsaicin. Here; we demonstrate that the potency and efficacy of AEA at VR1 receptors can be significantly increased by the concomitant activation of protein kinase A (PKA). In human embryonic kidney (HEK) cells over-expressing human VR1, AEA induces a rise in cytosolic Ca2+ concentration that is mediated by this receptor. The EC50 for this effect was decreased five-fold in the presence of forskolin (FRSK, 1-5 muM) or the cAMP analogue, 8-Br-cAMP (10-100 muM). The effects of 8-Br-cAMP and FRSK were blocked by a selective PKA inhibitor. The FRSK(10 nM) also potently enhanced the sensory neurone- and VR1-mediated constriction by AEA of isolated guinea-pig bronchi, and this effect was abolished by a PKA inhibitor. In rat dorsal root ganglia slices, AEA-induced release of substance P, an effect mediated by VR1 activation, was enhanced three-fold by FRSK (10 nM). Thus, the ability of AEA to stimulate sensory VR1, with subsequent neuropeptide release, appears to be regulated by the state of activation of PKA. This observation supports the hypothesis that endogenous AEA might stimulate VR1 under certain pathophysiological conditions.