downregulated

Downregulation is a biological process in which the level or activity of a gene product decreases in response to stimuli, developmental cues, or feedback mechanisms. It can affect RNA transcripts, the encoded proteins, or the function of cellular receptors and signaling pathways.

Mechanisms include transcriptional repression leading to lower mRNA synthesis, accelerated mRNA decay, reduced translation, or increased degradation of the protein. In membrane signaling, downregulation often involves receptor internalization and trafficking to endosomes or lysosomes, reducing the number of receptors on the cell surface and dampening responsiveness to ligands. Epigenetic changes can also contribute to longer-term downregulation by silencing gene expression.

Downregulation can occur rapidly, within minutes to hours, such as desensitization of G protein-coupled receptors after chronic ligand exposure, or more slowly through gene expression changes that unfold over days. Examples include insulin receptor downregulation with prolonged hyperinsulinemia, and epidermal growth factor receptor (EGFR) downregulation after sustained EGF exposure. Downregulation plays a role in normal physiology and in disease, influencing sensitivity to hormones, nutrients, or growth signals, and it can contribute to drug tolerance and resistance.

Researchers detect downregulation by measuring reduced mRNA levels (qPCR, RNA-seq), decreased protein abundance (Western blot, ELISA), or lower cell-surface receptor density (flow cytometry, surface biotinylation). It is important to distinguish between downregulation and simple inhibition of activity, as the former implies fewer functional molecules over time, often via changes in synthesis or trafficking.