I had asked a friend PhD neurobiologist to respond to a query in this forum,
which should be shared by those who might be interested.
with love and 'Carpe Diem'
Michel
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Subj: dopamine synthesis regulation
Dear Baldwin Robertson,
Your question on dopamine synthesis regulation was forwarded to me
by Michel Margosis. I've been out of the field for a while, and may not be
up to date on the latest advances, but I think I can help introduce you to
the basics. I hope that the following information can be of some use to
you.
- SR
Dopamine synthesis is regulated by a number of different mechanisms:
1) Tyrosine Hydroxylase is subject to end-product inhibition by free
dopamine within the nerve terminal. Dopamine exerts this feedback
inhibitory action by competing with the cofactor tetrahydrobiopterin for
its binding site on the tyrosine hyroxylase molecule. This same inhibitory
action can also be exerted by the dopamine metabolite commonly
referred to as DOPAC (3,4-dihydroxyphenylacetic acid, aka
3,4-dihydroxyphenylethylaldehyde). However, in the human brain,
(in contrast to other animals) DOPAC levels are normally very low,
and thus DOPAC may not have this effect physiologically in humans.
2) Dopamine released from neurons can inhibit tyrosine hydroxylase
activity indirectly, by acting at receptors located on the presynaptic
terminals of dopaminergic neurons. Chemical "second messengers" generated
within the dopaminergic neuron in response to the binding of dopamine to
the extracellular portion of its receptor mediate this effect, but, as far
as I know, the details of the molecules involved and the mechanism of
tyrosine hydroxylase inhibition have not been worked out. These
presynaptic receptors which regulate dopamine synthesis (and also dopamine
release) contribute to the maintenance of normal functioning during the
preclinical stages of Parkinson's disease, when symptoms are not observed
despite dramatic losses of dopaminergic cells. As dopaminergic neurons
die, the temporarily reduced levels of extracellular dopamine result in
reduced activation of the presynaptic receptors on remaining dopaminergic
neurons, and thus reduced inhibition of dopamine synthesis and release from
these neurons. The result is a greater dopamine synthesis in and release
from the remaining dopaminergic neurons, which compensates for the reduced
number of dopamine - releasing neurons, and helps maintain extracellular
dopamine levels at near normal levels until dopaminergic cell loss becomes
extreme.
3) During periods of increased activity of the dopaminergic neurons,
tyrosine hydroxylase may be converted to a state which has a higher
affinity for its cofactor tetrahydrobiopterin, and a lower affinity for the
end product inhibitor dopamine. This kinetic conversion involves a
phosphorylation of the tyrosine hydroxylase enzyme. Since the levels of
the cofactor are limiting to the synthetic reaction, the increase in the
enzyme's affity for the cofactor will result in an increased synthesis of
dopa and therefore of dopamine. This mechanism likely comes in to play in
late stages of Parkinson's Disease, when endogenous dopamine levels are
reduced to less than five percent of normal, and those dopaminergic neurons
remaining fire at an increased rate.
4) It has been suggested that an increased expression of tyrosine
hydroxylase protein may also result from the prolonged increases in the
firing activity likely to occur in remaining dopaminergic neurons during
late stages of Parkinson's Disease. To my knowlege, however, (which is
admittedly incomplete), this suggestion is based on experiments performed
in peripheral tissues, such as the adrenal medulla, and has not, at this
point been demonstrated to occur in brain dopaminergic neurons.
