Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1.
We have recently shown that lipid mediators of the emerging endocannabinoid system (ECS) are key players of growth control of the human pilosebaceous unit. In this study, we asked whether the prototypic endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) has a role in growth and survival of epidermal keratinocytes (KCs). Using human cultured KCs and skin organ-culture models, and by employing combined pharmacological and molecular approaches, we provide early evidence that AEA markedly suppresses KC proliferation and induces cell death, both in vitro and in situ. Moreover, we present that these cellular actions are mediated by a most probably constitutively active signaling mechanism that involves the activation of the metabotropic cannabinoid receptor CB(1) and a sequential engagement of the "ionotropic cannabinoid receptor" transient receptor potential vanilloid-1 (TRPV1). Finally, we demonstrate that the cellular effects of AEA are most probably due to a Ca(2+) influx via the non-selective, highly Ca(2+)-permeable ion channel TRPV1, and the concomitant elevation of intracellular Ca(2+) concentration. The data reported here may encourage one to explore whether the targeted manipulation of the above signaling pathway of the cutaneous ECS could become a useful adjunct treatment strategy for hyperproliferative human dermatoses such as psoriasis or KC-derived skin tumors.
Department of Physiology, Medical and Health Science Center, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
Balázs I
BI
Tóth
Nóra
N
Dobrosi
Angéla
A
Dajnoki
Gabriella
G
Czifra
Attila
A
Oláh
Attila G
AG
Szöllosi
István
I
Juhász
Koji
K
Sugawara
Ralf
R
Paus
Tamás
T
Bíró
D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D063388:Endocannabinoids; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002118:Calcium; C078814:anandamide