It is well known that
cytokinins are a class of
phytohormones that promote cell division in plant roots and shoots. However, their targets,
biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one
cytokinin,
zeatin riboside, can prevent
pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the
adenosine A(2A) receptor (A(2A)-R), which was blocked by an A(2A)-R antagonist and a
protein kinase A (
PKA) inhibitor, demonstrating the functional ability of
zeatin riboside by mediating through A(2A)-R signaling event. Since the A(2A)-R was implicated as a therapeutic target in treating
Huntington's disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that
zeatin riboside reversed mutant huntingtin (Htt)-induced
protein aggregations and
proteasome deactivation through A(2A)-R signaling.
PKA inhibitor blocked
zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated
proteasome activity and reduced mutant Htt
protein aggregations. However, a
proteasome inhibitor blocked both
zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A(2A)-R/PKA/
proteasome pathway. Taken together,
zeatin riboside might have therapeutic potential as a novel
neuroprotectant and a lead for treating
neurodegenerative disorders.