Anandamide as an intracellular messenger regulating ion channel activity.
The endocannabinoid anandamide (N-arachidonoylethanolamine) was proposed to be an extracellular retrograde messenger, which regulates excitability of neurons by cannabinoid CB1 receptor-dependent inhibition of neurotransmitter release. Recent findings indicate that the neuromodulatory actions of anandamide might be more complex. Anandamide has been shown to directly modulate various ion channels, such as alpha7-nicotinic acetylcholine receptors, T-type Ca2+ channels, voltage-gated and background K+-channels and Transient Receptor Potential Vanilloid type 1 (TRPV1) channels. The binding site of anandamide at some of these ion channels appears to be intracellular or at the bilayer interface. This rises the intriguing possibility that anandamide, prior to its release into the synaptic cleft, may regulate ion homeostasis and excitability of neurons as an intracellular modulator of ion channels independent of its action at cannabinoid CB1 receptors. This possibility might extend the concept of anandamide as an endocannabinoid retrograde messenger and may have profound implications for its role in neurotransmission and neuronal function. Here, we will review the evidence for this hypothesis.
van der Stelt
Mario
M
Endocannabinoid Research Group, Istituto Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Bldg. 70, 80078 Pozzuoli (NA), Italy.
Di Marzo
Vincenzo
V
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D063388:Endocannabinoids; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D007477:Ions; D008051:Lipid Bilayers; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D007473:Ion Channels; D007477:Ions; D008051:Lipid Bilayers; D018377:Neurotransmitter Agents; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002118:Calcium; C078814:anandamide