A role for p53 in the regulation of lysosomal permeability by delta 9-tetrahydrocannabinol in rat cortical neurones: implications for neurodegeneration.
The psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), can evoke apoptosis in cultured cortical neurones. Whilst the intracellular mechanisms responsible for this apoptotic pathway remain to be fully elucidated, we have recently identified a role for the CB1 type of cannabinoid (CB) receptor and the tumour suppressor protein, p53. In the current study, we demonstrate the Delta9-THC promotes a significant increase in lysosomal permeability in a dose- and time-dependent manner. The increase in lysosomal permeability was blocked by the CB1 receptor antagonist, AM251. Delta9-THC increased the localization of phospho-p53Ser15 at the lysosome and stimulated the release of the lysosomal cathepsin enzyme, cathepsin-D, into the cytosol. The p53 inhibitor, pifithrin-alpha and small interfering RNA-mediated knockdown of p53 prevented the Delta9-THC-mediated increase in lysosomal permeability. Furthermore, the Delta9-THC -mediated induction of apoptosis was abrogated by a cell-permeable cathepsin-D inhibitor (10 microM). Thus, the study demonstrates that Delta9-THC impacts on the lysosomal system, via p53, to evoke lysosomal instability as an early event in the apoptotic cascade. This provides evidence for a novel link between the CB1 receptor and the lysosomal branch of the apoptotic pathway which is crucial in regulating neuronal viability following exposure to Delta9-THC.
Gowran
Aoife
A
Department of Physiology and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
Campbell
Veronica A
VA
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D013759:Dronabinol / Q000493:pharmacokinetics* / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D043884:Receptor, Cannabinoid, CB1; D016159:Tumor Suppressor Protein p53; D013759:Dronabinol