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The vanilloid receptor (VR1)‐mediated effects of anandamide are potently enhanced by the cAMP‐dependent protein kinase
Author(s) -
De Petrocellis Luciano,
Harrison Selena,
Bisogno Tiziana,
Tognetto Michele,
Brandi Ines,
Smith Graham D.,
Cremi Cristophe,
Davis John B.,
Geppetti Pierangelo,
Di Marzo Vincenzo
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00406.x
Subject(s) - anandamide , cannabinoid receptor , chemistry , trpv1 , endocrinology , medicine , receptor , capsaicin , protein kinase a , agonist , capsazepine , cannabinoid , gi alpha subunit , endocannabinoid system , neuropeptide , g protein , kinase , biology , biochemistry , transient receptor potential channel
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 Ca 2+ concentration that is mediated by this receptor. The EC 50 for this effect was decreased five‐fold in the presence of forskolin (FRSK, 1–5 µ m ) or the cAMP analogue, 8‐Br‐cAMP (10–100 µ m ). The effects of 8‐Br‐cAMP and FRSK were blocked by a selective PKA inhibitor. The FRSK (10 n m ) 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 n m ). 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.