Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels.
The endocannabinoid anandamide is able to interact with the transient receptor potential vanilloid 1 (TRPV1) channels at a molecular level. As yet, endogenously produced anandamide has not been shown to activate TRPV1, but this is of importance to understand the physiological function of this interaction. Here, we show that intracellular Ca2+ mobilization via the purinergic receptor agonist ATP, the muscarinic receptor agonist carbachol or the Ca(2+)-ATPase inhibitor thapsigargin leads to formation of anandamide, and subsequent TRPV1-dependent Ca2+ influx in transfected cells and sensory neurons of rat dorsal root ganglia (DRG). Anandamide metabolism and efflux from the cell tonically limit TRPV1-mediated Ca2+ entry. In DRG neurons, this mechanism was found to lead to TRPV1-mediated currents that were enhanced by selective blockade of anandamide cellular efflux. Thus, endogenous anandamide is formed on stimulation of metabotropic receptors coupled to the phospholipase C/inositol 1,4,5-triphosphate pathway and then signals to TRPV1 channels. This novel intracellular function of anandamide may precede its action at cannabinoid receptors, and might be relevant to its control over neurotransmitter release.
van der Stelt
Mario
M
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy.
Trevisani
Marcello
M
Vellani
Vittorio
V
De Petrocellis
Luciano
L
Schiano Moriello
Aniello
A
Campi
Barbara
B
McNaughton
Peter
P
Geppetti
Piero
P
Di Marzo
Vincenzo
V
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D007473:Ion Channels / Q000502:physiology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides; D058913:Purinergic Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels; D019284:Thapsigargin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D007473:Ion Channels; D018721:Muscarinic Agonists; D053284:Polyunsaturated Alkamides; D058913:Purinergic Agonists; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002217:Carbachol; D010738:Type C Phospholipases; D000252:Calcium-Transporting ATPases; D002118:Calcium; C078814:anandamide