Studies of Noradrenaline Biosynthesis in Nerve Tissue

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Abstract
Results recently obtained in studies of the invitrosynthesis of noradrenaline from tyrosine, dopa and dopamine in various fractions of the bovine splenic nerve homogenate are reviewed. It is concluded that the first two steps in noradrenaline synthesis take place extragranularly, while the last step, the β‐hydroxylation of dopamine, occurs in the granules. Evidence is presented that noradrenaline synthesis may be feed‐back regulated, not only extragranularly by product inhibition of the hydro‐ xylation of tyrosine, but also at the granule level, by competitive inhibition of dopamine penetration to the β‐hydroxylation sites. The newly synthesized noradrenaline appears to be stored separately from the major endogenous noradrenaline store, in a compartment of limited capacity, possibly located in the granule membrane. This membrane appears to have a limited permeability to amines, the passage of tracer amounts of amines being competitively inhibited both by dopamine or noradrenaline in the medium, and by reserpine. Studies of the “wash fraction” in these experiments support the concept that deamination to a large extent occurs in the “granule fraction”, which according to morphological evidence appears to be largely free from contamination with mitochondria. This suggests that monoamine oxidase may be located not only in mitochondria, but also in the noradrenaline storing granules themselves. The results also suggest the existence of several distinct “pools” of noradrenaline in the preparation. The possibility is discussed that monoamine oxidase may attack only one of these “pools”, the non‐bound intragranular amines, while the amines in the remaining “pools” may be protected against this enzyme, either by binding or by staying extragranularly. The results are summarized diagrammatically in a proposed model of the sympathetic neuro‐effector junction.