Biochemistry Of Ne

NE synthesis starts in the cytosol and ends in synaptic vesicles, where it is stored at extremely high concentrations (100 mM in vesicles versus a few micromolar in the cytosol). The release of NE from synaptic vesicles is triggered by the arrival of an action potential. Its removal from the extracellular space is due to very efficient re-uptake (about 80% of the NE released is re-uptaken in the synaptic terminals). NE essentially is finally metabolized by a monoamine oxidase (MAO) into dihydroxyphenylglycol (DHPG). A small amount of NE is re-uptaken in nonneuronal cells and metabolized by catechol-O-methyltransfer-ase (COMT) (Fig. 2).

Biochemistry The Brain

Figure 2 Noradrenergic synapse. NE is synthetized from the amino acid tyrosine (Tyr) via three enzymes, tyrosine hydroxylase (TH), l-aromatic amino acid decarboxylase (l-AADC), and dopamine-b-hydroxylase (DBH). NE and dopamine (DA) are transported in vesicles through the vesicular monoamine transporter (VMAT). After release from synaptic vesicles, NE is re-uptaken by the NE transporter (NET) and further metabolized by the monoamine oxidase (MAO) into dihydrophenylglycol (DHPG). DOPA: dihydroxyphenylalanine.

Figure 2 Noradrenergic synapse. NE is synthetized from the amino acid tyrosine (Tyr) via three enzymes, tyrosine hydroxylase (TH), l-aromatic amino acid decarboxylase (l-AADC), and dopamine-b-hydroxylase (DBH). NE and dopamine (DA) are transported in vesicles through the vesicular monoamine transporter (VMAT). After release from synaptic vesicles, NE is re-uptaken by the NE transporter (NET) and further metabolized by the monoamine oxidase (MAO) into dihydrophenylglycol (DHPG). DOPA: dihydroxyphenylalanine.

A. NE Synthesis and Storage

NE is synthesized from the amino acid tyrosine. Four enzymes are necessary (Fig. 3). The first, tyrosine hydroxylase (TH), converts tyrosine to L-dihydroxy-phenylalanine (l-DOPA). This enzyme is rate-limiting for the synthesis of both NE and dopamine. It requires a reduced pteridine (Pt-2H) cofactor, regenerated from pteridine (Pt) by another enzyme, pteridine reductase, which is not specific to neurons. TH is subject to multiple controls. Short-term regulation includes activation of TH in response to increased nerve traffic and negative feedback control through end-product (i.e., dopamine and NE) inhibition. Short-term activation of TH involves phosphorylation at four sites corresponding to serine residues 8,19,31, and 40 in the rat sequence. In particular, the phosphorylation of serine 40 increases the dissociation rate between TH and its endogenous inhibitor. Long-term regulation involving the production of new TH enzyme occurs at the level of transcription and translation in response to various stimuli via three main second messengers: cyclic AMP, diacylglycerol, and calcium. Nerve growth factor and cell-cell contacts are important during development to promote and maintain the catecholaminergic phenotype, and neurotransmitters and glucocorticoids mediate the activation of TH in response to environmental changes such as stress and exposure to certain drugs such as reserpine, nicotine, or cocaine.

l-DOPA is decarboxylated by a nonspecific L-aromatic amino acid decarboxylase to give dopa-mine and carbon dioxide. Dopamine is then transported into vesicles by the vesicular monoamine transporter (VMAT) using the proton electrochemical gradient across the vesicle membrane.

Finally, dopamine b-hydroxylase (DBH), which is localized in a membrane-bound (77-kDa) or soluble

Figure 3 NE synthesis and metabolism. NE is synthetized from the amino acid tyrosine. Tyrosine is transformed into l-dihydroxyphenylalanine (l-DOPA), together with the oxidation of a cofactor, reduced pteridine (Pt-2H). Pteridine is regenerated by pteridine reductase. l-DOPA is decarboxylated by the l-aromatic amino acid decarboxylase to form dopamine. Dopamine is converted to NE by dopamine-b-hydroxylase. In adrenergic cells, phenylethanolamine-N-methyltransferase methylates NE to form epinephrine. In the case of dopamine-b-hydroxylase defiency, NE can be synthesized from dihydroxyphenylserine (DOPS), which is decarboxylated by the l-aromatic amino acid decarboxylase to form NE. NE is metabolized by monoamine oxidase into dihydroxyphenylglycolaldehyde, which is immediately reduced to dihydroxyphenylglycol (DHPG). Dihydroxyphenylglycol is methylated by catechol-O-methyl transferase to form methoxyhy-droxyphenylglycol (MHPG).

Figure 3 NE synthesis and metabolism. NE is synthetized from the amino acid tyrosine. Tyrosine is transformed into l-dihydroxyphenylalanine (l-DOPA), together with the oxidation of a cofactor, reduced pteridine (Pt-2H). Pteridine is regenerated by pteridine reductase. l-DOPA is decarboxylated by the l-aromatic amino acid decarboxylase to form dopamine. Dopamine is converted to NE by dopamine-b-hydroxylase. In adrenergic cells, phenylethanolamine-N-methyltransferase methylates NE to form epinephrine. In the case of dopamine-b-hydroxylase defiency, NE can be synthesized from dihydroxyphenylserine (DOPS), which is decarboxylated by the l-aromatic amino acid decarboxylase to form NE. NE is metabolized by monoamine oxidase into dihydroxyphenylglycolaldehyde, which is immediately reduced to dihydroxyphenylglycol (DHPG). Dihydroxyphenylglycol is methylated by catechol-O-methyl transferase to form methoxyhy-droxyphenylglycol (MHPG).

form (73-kDa) in the synaptic vesicles, converts dopamine to NE. Both forms of DBH arise from a single translational product. The 77-kDa form has an uncleaved signal sequence. DBH gene expression is activated by a subset of conditions that elevate TH gene expression, but DBH gene expression often requires more severe and more prolonged treatment than TH. In the adrenal medulla and also in sparse neurons located in the central nervous system, a fifth enzyme, phenylethanolamine-N-methyltransferase, methylates NE to form epinephrine.

Was this article helpful?

0 0
Stop Smoking, Kick The Habit Now

Stop Smoking, Kick The Habit Now

Now You Can Quit Smoking And Start Living a Healthy Life Yes, You! Have You Ever Thought There’s No Way You Can Give Up Cigarettes Without Losing Your Mind? Well, Worry No More.

Get My Free Ebook


Post a comment