Regulation of Norepinephrine Biosynthesis

Abstract

In addition to its ability to release norepinephrine consequent to stimula­ tion, the adrenergic neuron can carry out a variety of functions related to the metabolism of its neurotransmitter. Both the adrenal medulla chromaffin cells (1-3) and the adrenergic neuron (3-5) store norepinephrine within vesicles which exhibit a characteristic dense core as seen in electron micro­ graphs which have been appropriately fixed prior to examination (6-14). Studies on isolated chromaffin granules and adrenergic vesicles have shown that the storage of catecholamines is associated with an active uptake pro­ cess from the adjacent cytoplasm (15-17). This uptake process appears to require A TP and Mg++ and is selectively inhibited by catecholamine deplet­ ing agents of the reserpine type (15, 16). In addition to the uptake process into isolated vesicles, the neuron concentrates norepinephrine across the ax­ onal membrane (18). This process is not inhibited by reserpine (19), but may be selectively blocked by other agents, among which are cocaine, imi­ pramine, and desmethylimipramine (20-23). The uptake of the catechol a­ mines and other phenylethylamines across the axonal membrane is a very rapid and efficient process. It is generally believed that this uptake is respon­ sible for the termination of the biological actions of either released or ad­ ministered catecholamines. Blockade of this uptake process leads to the po­ tentiation of the actions of norepinephrine and epinephrine (24-26). Norepinephrine is stored within chromaffin granules or adrenergic vesi­ cles largely in a bound form (27-30). The catecholamines appear to interact with ATP (31-34), resulting in the formation of a tetracatecholamine-ATP complex (35). This salt complex presumably is further bound to soluble proteins, the chromogranins, within the storage particle, although there is no direct evidence for the formation of a quantitatively significant complex (30, 36-38). Nevertheless, the ability of labelled catecholamines to enter the storage particles without exchanging with the bulk of the endogenous stores