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J. Cell Biol. 160 (4): 481-486

Copyright © 2003 by the Rockefeller University Press.

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The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response

Emma-Jane Williams1, Frank S. Walsh2, and Patrick Doherty1

1 Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, London SE1 1UL, UK
2 Discovery Research, Wyeth Research, Collegeville, PA 19426

Address correspondence to Patrick Doherty, Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, New Hunt's House, London Bridge, London SE1 1UL, UK. Tel.: 44-207-848-6813. Fax: 44-207-848-6816. E-mail: patrick.doherty{at}kcl.ac.uk

Abstract: Akey role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities.

Key Words: CAM; CB1; 2-AG; cannabinoid; N-cadherin

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