Differential down-regulation of alpha-2 adrenergic receptor subtypes

The regulation of G protein-coupled receptor expression is important in the physiology of an organism and can occur at any of the steps between gene transcription to turnover of the receptor protein itself. Agonist stimulation causes receptor desensitization, which is characterized by a rapid reduction in response to the agonist. Down-regulation often occurs after prolonged agonist treatment and is manifested as a decrease in receptor density. Short term desensitization results from a rapid (in minutes) and reversible uncoupling of the receptor-G protein complex, followed by sequestration and/or internalization of receptors from the cell surface. Receptors are not degraded as removal of agonist rapidly restores receptor function. Down-regulation, on the other hand, displays a much longer time-course (hours to days) and is characterized by a decrease in receptor density as determined by radioligand binding. Removal of agonist will only slowly reverse down-regulation, because new receptor synthesis is required in most cases (1;2). The mechanism of receptor down-regulation is not well understood, but may include an accelerated rate of removal of receptors, a decrease in the rate of appearance of receptors, or both. Our previous studies have shown significant differences in the concentration of agonist required to produce down-regulation of alpha-2 adrenergic receptor subtypes (3;4). Here we review the mechanisms and molecular determinants for receptor down-regulation as well as our own data exploring the subtype-specific differences in alpha-2 receptor down-regulation. We find that the extent and time-course of agonist-induced down-regulation occurs in a similar fashion regardless of the receptor subtype or the cell line in which it is expressed. The mechanism for receptor down-regulation in all cases is an increase in the rate of receptor disappearance.