what is down-regulation?
neil.fournier at sympatico.ca
Thu Jan 29 02:28:41 EST 2004
My response is below (I apologize for any typos):
Down-regulation is the typical response of a receptor(s) to the increased
extracellular circulation of a particular ligand for that receptor. There
is generally a subsequent decrease in the density and number of receptors
due to the increased or prolonged presence of a ligand (or a drug) within
extracellular space that surrounds as receptor(s). This is generally
assayed through the use of in situ hybridization histochemical techniques (a
technique that measures the particular expression of a mRNA sequence
expressed by a specific receptor), or through the use of autoradiography.
So typically following the exposure to a stressor, the subsequent release of
cortisol (or corticosterone in rats) will presumably stimulate a variety of
glucocorticoid receptors. Cells (neurons) regulate their activity through
altering the density of receptor sites that can potentially be stimulated by
the endogenous chemical (in this case by corticosterone). The result is
typically a decrease in the number of glucocorticoid receptors (or
mineralocorticoid receptors: another receptor that corticosterone can bind
too) found along membrane sites of the neuron. This decrease will "shunt"
the stimulatory activity at this receptor site because it is now occluded.
A good study to review is the recent work of McNally and Akil (I think it
was published in 2003 in Brain Research or something) on the effects of
opiate-withdrawal and down-regulation of glucocorticoid receptors within the
In your question the comment for post-traumatic stress becomes a little
difficult. Chronic exposures to elevated levels of circulating
glucocorticoids can alter many aspect of receptor function. Typically
down-regulation occurs through processes that involve homologous and
heterologous desensitization (basically a fancy way of saying "loss of
function") . However, there can often be compensatory changes among
different receptor sites as a result of the chronic down-regulation of
another receptor. In this case, the compensatory change at a secondary
receptor system could display compensatory overshooting processes, in terms
of sensitivity (similar to a routinely observed between the sympathetic and
parasympathetic autonomic systems) or even electrical sensitivity (i.e.
increased expression of specific ion channels). The problem with increased
levels of circulating glucocorticoids are the indirect effects involving
other receptor systems (for example 5-HT, NE, or opioid, orexin, etc etc
etc.) and the immunosuppressive actions that normally accompany prolonged
elevations of corticosteroids.
Unfortunately, that is not the only process that may take place. In the
case of acute stress the opposite effect may occur. That is an increase in
neuronal density of a particular receptor(s) (i.e. a up-regulation),
resulting in some transient alteration in the electrical nature of the cell.
>From this perspective some of the typical observations of improved
performance in animals and humans under cases of mild acute stress makes a
lot of functional sense (review the ("in")famous Yerkes-Dobson law).
One argument made in cases of prolonged stress is that a form of
neurophysiological compensation can be made to the increased plasma levels
of circulating glucocorticoids (an argument reinforced by many recording
studies). Thus from this argument prolonged exposures to stress will result
in a eventual habituation of neuronal ensembles to the circulating levels
of elevated glucocorticoids. However, this concept is at odds with some of
the results that have shown increased electrical lability in animals and
humans following prolonged exposures to chronic stress (i.e. an increased
incidence of epileptiform or seizure activity. In response to your
post-traumatic stress question, seizures are commonly reported by patients.
Moreover, stress has been shown to aggravate seizure frequency and severity.
In this regard, prolonged stress can lead to a readjustment of the normal
homeostatic balance of excitatory vs. inhibitory processes within the
One problem that has proliferated in this area of research is this
preconceived notion that stress is always a negative or aversive thing.
Generally speaking it usually is. However, the more appropriate and
accurate view is that it is not the stress, per se, but the type of stressor
that will determine the actual severity and response (i.e. positive or
negative) observed by neuronal systems and the organism. This explains
the disparity found between studies that investigate the neuronal
consequences of stress. The context of the stress and the type of stressor
are the key variables.
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