Mechanisms of Regulation of Receptor Function
The regulation of receptor function is associated closely with the plasticity of signal transduction. The homeostasis of signal transduction is a prerequisite for emotional health. Signal transduction appears to be destabilized in patients who have emotional and cognitive disorders. Receptors are regulated at the level of their gene expression (by transcription or translation) and by posttranslational covalent modifications (eg, phosphorylation). In general, the density of receptors is upregulated in response to a decrease of their corresponding neurotransmitters and downregulated in response to an increase of the neurotransmitter. For example, ß-adrenoceptor density increases after depletion of norepinephrine by reserpine and decreases after the blocking of norepinephrine reuptake by antidepressants. The phenomenon of receptor desensitization has been studied extensively in the ß-adrenoceptor–G protein–coupled adenylate cyclase system. The desensitization of the ß-adrenoceptor–G protein–coupled adenylate cyclase system is accomplished by receptor phosphorylation. Two types of protein kinases are involved in receptor phosphorylation: PKA, activated by cAMP; and a second messenger–independent G protein–coupled protein kinase, beta-adrenergic receptor kinase (BARK 1). BARK 1 phosphorylates G protein–coupled receptors (such as the ß-adrenoceptor), predominantly when they are occupied by agonists. BARK 1–mediated phosphorylation has also been implicated in the sequestration of ß-adrenoceptors. Furthermore, the 5-HT2C receptor is phosphorylated by agonist treatment, which results in desensitization of receptor signaling.
Different receptor systems “cross-talk” at different levels of their signal transduction cascade. Heteroreceptor regulation is widespread, and the interdependence of norepinephrine and 5-HT in the synaptic pharmacology of antidepressants is of particular in-terest. For example, supersensitivity to 5-HT and dopamine, demonstrated electrophysiologically or behaviorally following chronic administration of antidepressants or electroconvulsive therapy, is prevented by experimentally lesioning noradrenergic neurons. Furthermore, changes in cortical ß-adrenoceptor density modify 5-HT2A-mediated behavior in a manner that is independent of changes in 5-HT2A receptor number. Studies with the dual-uptake inhibitor venlafaxine have demonstrated a link between the two aminergic signal transduction pathways beyond the ß-adrenoceptors. Venlafaxine failed to desensitize the ß-adrenoceptor-coupled adenylate cyclase sys-tem unless 5-HT in brain was depleted. PKC, activated via 5-HT2A or 5-HT2C receptors, has been hypothesized to modify the PKA-mediated regulation of ß-adrenoceptor sensitivity. Such counterregulation between prominent kinases on agonist-induced desensitization of ß-adrenoceptors has been demonstrated in various cell lines.