CAMs Stimulate Neurite Growth through Endocannabinoids

Abstract

Williams et al. investigated the role of 2-arachidonylglycerol (2-AG) in mediating the response to cell adhesion molecules (CAMs) and uncovered evidence for a surprising new role for endocannabanoids in coupling CAM signaling to neurite outgrowth. CAMs, such as N-cadherin, neural CAM, and L1, promote axonal growth by activating a fibroblast growth factor receptor (FGFR)-signaling pathway involving phospholipase Cγ-mediated generation of diacylglycerol (DAG) and the subsequent cleavage of DAG by a DAG lipase to generate 2-AG. 2-AG, which is a ligand for the cannabinoid CB1 receptor, is then hydrolyzed to arachidonic acid (AA). Activation of the FGFR pathway stimulates calcium influx into the growth cone, a process that has been implicated in axonal guidance. The intermediate steps coupling DAG hydrolysis to calcium influx and which of the two second messengers, AA and 2-AG, mediates the response, have remained unclear. Antagonists to the CB1 receptor inhibited neurite outgrowth in cultured cerebellar neurons stimulated with N-cadherin or FGF2, whereas CB1 agonists stimulated neurite outgrowth. Neurite outgrowth in response to CB1 agonists was unaffected by an FGFR inhibitor, but was inhibited by N- and L- type calcium channel blockers. Neither CB1 antagonists nor calcium channel blockers inhibited neurite outgrowth stimulated by brain-derived growth factor, which acts through the TrkB receptor. These data suggest a novel role for endocannabinoid signaling in mediating neurite outgrowth during development. E.-J. Williams, F. S. Walsh, P. Doherty, The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol . 160 , 481-486 (2003). [Abstract] [Full Text]