Up- and Down-regulation of Noradrenergic Receptor Systems in Brain: Molecular Mechanisms and Physiological Significance

The data reviewed in this paper demonstrate that the norepinephrine (NE) receptor coupled adenylate cyclase system in brain displays all the characteristics of a functional receptor system including recognition function and action function, with β-adrenergic receptors representing a subpopulation of NE receptors. Though up- and down-regulation of the system appear to be inversely related to the availability of the agonist NE at the receptor site, the NE signal input per se is not the only prerequisite to elicit changes in sensitivity to NE and in the density of β-adrenergic receptors. Subsensitivity to NE is not invariably linked to a decrease in the Bmax value of β-adrenergic receptors suggesting that a two step phenomenon is also operating in brain, one being the modification of the coupling between receptor and adenylate cyclase and the other the actual loss of β-adrenergic receptors. The molecular basis of both phenomena has yet to be elucidated in the central nervous system. Steroid hormones (adrenal corticoids, sex steroids) are also involved in the regulation of central noradrenergic sensitivity. Since the cascade of cyclic AMP mediated events functions as a highly effective kinetic amplificational mechanism, small changes in the membrane transfer of the NE input signal will be amplified and make the NE receptor coupled adenylate cyclase system in brain an integral part in the processing of the NE signal and perhaps of other receptor mediated signals.