DownRegulation

Downregulation is a cellular process by which a cell decreases its response to a molecule, often by reducing the number or activity of receptors or signaling components involved in the response. It is a form of adaptation that can occur in signaling pathways in response to chronic stimulation.

Mechanisms include receptor endocytosis and lysosomal or proteasomal degradation, receptor ubiquitination, and decreased receptor synthesis. In many cases, a ligand binds a receptor, triggering phosphorylation by G protein-coupled receptor kinases and recruitment of beta-arrestins, leading to receptor internalization. Receptors may be recycled back to the surface or degraded, reducing the total receptor pool. Downstream signaling instruments can also be downregulated, including reduced transcription of target genes.

Examples include GPCRs such as beta-adrenergic receptors, receptor tyrosine kinases like EGFR, and insulin receptors. Pharmacologically, chronic exposure to an agonist can cause downregulation and tolerance, whereas desensitization may occur more rapidly without loss of receptor numbers. Downregulation can be reversible if receptors are recycled or resynthesized.

Clinical relevance includes drug tolerance and insulin resistance; certain cancers can involve altered receptor expression. Measurement of receptor density or signaling activity is used to study downregulation, using methods such as ligand binding assays or Western blotting.