MOLECULAR MECHANISM OF ADRENERGIC PLASTICITY

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One of the basic principles important to the function of excitable neurosecretory cells is that the strength of synaptic activity modulates the secretory capacity of the cells. One of the best examples of this kind of biochemical neuroplasticity is the modulation of catecholamine synthesis which occurs in response to increased afferent neural activity in the peripheral and central nervous systems. In the peripheral nervous system, for example, both the short- and long-term activity of the rate-limiting enzyme in the catecholamine synthetic pathway, tyrosine hydroxylase, is modulated by cholinergic activity. In our previous studies, we focused on the short-term regulation of this enzyme using a convenient model system, isolated bovine adrenal chromaffin cells. Recently we have established that not only is short-term cholinergic regulation expressed in these cells, but also that the levels of tyrosine hydroxylase mRNA, and protein are modulated in response to cholinergic receptor occupancy. In the research presented in this application, we will utilize this in vitro induction of tyrosine hydroxylase levels by cholinergic agonists to understand and characterize the molecular mechanisms controlling the increased level of tyrosine hydroxylase mRNA and protein. We will determine the role of cholinergic receptor occupancy in regulating the level of tyrosine hydroxylase mRNA synthesis and the translation of this message into tyrosine hydroxylase enzyme protein. We will establish the basis for the temporal disparity between the time course of the increase in message level and the increase in tyrosine hydroxylase enzyme activity. Lastly, we will evaluate the role of ribonucleotide sequences within the untranslated region of tyrosine, hydroxylase mRNA in influencing the translation efficiency of the tyrosine hydroxylase message.