Sci. STKE, 25 February 2003
Neuronal Development CAMs Stimulate Neurite Growth through Endocannabinoids
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 C-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.
Citation: CAMs Stimulate Neurite Growth through Endocannabinoids. Sci. STKE 2003, tw89 (2003).
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