Selective adrenergic/cyclic AMP-dependent switch-off of proteasomal proteolysis alone switches on neural signal transduction: An example from the pineal gland

The molecular processes underlying neural transmission are central issues i n neurobiology. Here we describe a novel mechanism through which noradrenal ine (NA) activates its target cells, using the mammalian pineal organ as a model. In this neuroendocrine transducer, NA stimulates arylalkylamine N-ac etyltransferase (AANAT; EC 2.3.1.87), the key enzyme regulating the nocturn al melatonin production. In rodents, AANAT protein accumulates as a result of enhanced transcription, but in primates and ungulates, the AANAT mRNA le vel fluctuates only marginally, indicating that other mechanisms regulate A ANAT protein and activity. These were investigated in cultured bovine pinea locytes. AANAT mRNA was readily detectable in unstimulated pinealocytes, an d levels did not change following NA treatment. In contrast, NA increased A ANAT protein levels in parallel with AANAT activity, apparently through a c yclic AMP-mediated mechanism. Immunocytochemistry revealed that the changes in AANAT protein levels occurred in virtually all pinealocytes. Inhibition of AANAT degradation by proteasomal proteolysis alone was found to switch- on enzyme activity by increasing AANAT protein levels five- to 10-fold. Acc ordingly, under unstimulated conditions AANAT protein is continually synthe sized and immediately destroyed by proteasomal proteolysis. NA appears to a ct via cyclic AMP to protect AANAT from proteolytic destruction, resulting in accumulation of the protein. These findings show that tightly regulated control of proteasomal proteolysis of a specific protein alone can play a p ivotal role in neural regulation.