The Endogenous Cannabinoid Anandamide Inhibits α7 Nicotinic Acetylcholine Receptor-Mediated Responses in Xenopus Oocytes
2003
The effect of the endogenous cannabinoid ligand anandamide on the function
of the cloned α 7 subunit of the nicotinic acetylcholine (ACh)
receptor expressed in Xenopus oocytes was investigated by using the
two-electrode voltage-clamp technique. Anandamide reversibly inhibited
nicotine (10 μM) induced-currents in a concentration-dependent manner (10
nM to 30 μM), with an IC 50 value of 229.7 ± 20.4 nM. The
effect of anandamide was neither dependent on the membrane potential nor
meditated by endogenous Ca 2 + dependent Cl - channels since it was unaffected by intracellularly injected BAPTA and
perfusion with Ca 2 + -free bathing solution containing 2
mM Ba 2 + . Anandamide decreased the maximal
nicotine-induced responses without significantly affecting its potency,
indicating that it acts as a noncompetitive antagonist on nicotinic
acetylcholine (nACh) α 7 receptors. This effect was not
mediated by CB 1 or CB 2 receptors, as neither the
selective CB 1 receptor antagonist
N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboximide
hydrochloride (SR 141716A) nor CB 2 receptor antagonist
N -((1 S )-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide
(SR 144528) reduced the inhibition by anandamide. In addition, inhibition of
nicotinic responses by anandamide was not sensitive to either pertussis toxin
treatment or to the membrane permeable cAMP analog 8-Br-cAMP (0.2 mM).
Inhibitors of enzymes involved in anandamide metabolism including
phenylmethylsulfonyl fluoride, superoxide dismutase, and indomethacin, or the
anandamide transport inhibitor AM404 did not prevent anandamide inhibition of
nicotinic responses, suggesting that anandamide itself acted on nicotinic
receptors. In conclusion, these results demonstrate that the endogenous
cannabinoid anandamide inhibits the function of nACh α 7 receptors expressed in Xenopus oocytes in a cannabinoid
receptor-independent and noncompetitive manner.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
50
References
57
Citations
NaN
KQI