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Received for publication July 28, 2006.
Revised December 15, 2006.
Accepted for publication December 15, 2006.
In central neurons the cell-surface distribution of cannabinoid receptor subtype-1 (CB1) is highly polarized towards axons and at synaptic terminals, where it is well positioned to modulate neurotransmitter release. Recently it has been suggested that CB1 receptor axonal targeting is mediated by high levels of constitutive activity leading to domain-specific endocytosis. We have investigated further the mechanisms that underlie CB1 receptor axonal polarization in hippocampal neurons and find that constitutive activity is not an essential requirement for this process. We demonstrate that the cell-surface distribution of a N-terminally tagged, fluorescent CB1 receptor fusion-protein is almost exclusively localized to the axon when expressed in cultured hippocampal neurons. Inhibition of endocytosis by co-transfection with a dominant-negative dynamin-1 (K44A) mutant traps both recombinant and endogenous CB1 receptors at the somatodendritic cell-surface. However, this effect could not be mimicked by inhibiting constitutive activity or receptor activation, either by expressing mutant receptors that lack these properties or treatment with CB1 receptor antagonists possessing inverse agonist activity. These data are consistent with a revised model in which domain-specific endocytosis regulates the functional polarization of CB1 receptors, but that this process is distinct from constitutive activity.
Key words:
Cannabinoid, Gi family, Receptor synthesis/trafficking, Molecular dynamics, Immunocytochemistry
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