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First published on July 12, 2007; DOI: 10.1124/mol.107.036939

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Received for publication April 11, 2007.
Revised July 12, 2007.
Accepted for publication July 12, 2007.

The Endocannabinoid Anandamide Inhibits the Function of {alpha}4{beta}2 Nicotinic Acetylcholine Receptors

Charles E. Spivak 1*, Carl R. Lupica 2, Murat Oz 3

1 NIDA Intramural Research Program 2 NIH/NIDA 3 NIDA/IRP

* Address correspondence to: E-mail: cspivak{at}intra.nida.nih.gov

Abstract

The effects of the endocannabinoid anandamide (arachidonylethanolamide, AEA) on the function of {alpha}4{beta}2 nicotinic acetylcholine receptors (nAChR) stably expressed in SH-EP1 cells were investigated using the whole-cell patch clamp technique. In the concentration range of 200 nM to 2 µM, AEA significantly reduced the maximal amplitudes and increased the desensitization of ACh-induced currents. The effects of AEA could be neither replicated by the exogenous cannabinoid {Delta}9-tetrahydrocannabinol ({Delta}9-THC, 1 µM), nor reversed by the selective CB1 receptor antagonist SR-141716A (1 µM). The actions of AEA were apparent when applied extracellularly, but not during intracellular dialysis. Furthermore, the effects of AEA on ACh currents were not altered by the calcium chelator BAPTA. The onset and washout of the AEA effects required several minutes (10-30 min), but the latter was significantly decreased in the presence of lipid free bovine serum albumin (BSA). Moreover, BSA alone increased peak ACh current amplitudes and diminished desensitization rates in naive cells, suggesting a tonic modulation of {alpha}4{beta}2 nAChR function by an endogenous AEA-like lipid. Further analysis of AEA effects on {alpha}4{beta}2 nAChR mediated currents, using a two-stage desensitization model, indicated that the first forward rate constant leading to desensitization, k1, increased nearly 30-fold as a linear function of the AEA concentration. In contrast, the observation that the other three rate constants were unaltered by AEA suggested that AEA raised the energy of the activated state. These results indicate that AEA directly inhibits the function of {alpha}4{beta}2 nAChRs in a CB1-receptor independent manner.


Key words: Cannabinoid, Nicotinic cholinergic, Ion channel regulation, Desensitization/uncoupling, Thermodynamic and kinetic processes and modeling


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