desensitization

Desensitization is a receptor turning down its own sensitivity while it is being stimulated, the way your eyes stop noticing a constant smell or your fingers stop feeling a watch you have worn all day. Even though the drug is still present and still bound, the response wanes — the receptor has, in effect, stopped paying full attention.

At the molecular level this is an active, regulated process, not mere fatigue. For G-protein-coupled receptors, the classic sequence is: the activated receptor is tagged by kinases, then bound by proteins called arrestins that uncouple it from its G protein, and finally pulled inside the cell (internalized) where it is either recycled back or degraded. The result is fewer working receptors at the surface and weaker signaling, often within minutes to hours.

Desensitization is one of the molecular roots of tolerance, but they are not synonyms: desensitization is a specific receptor-level phenomenon, while tolerance is the broader, whole-body fading of effect that may also involve faster metabolism and other adaptations. It can be homologous (only the stimulated receptor is affected) or heterologous (a shared downstream step is dampened, so related receptors lose responsiveness too). For drug designers, understanding it matters: an agonist that strongly drives internalization may lose its punch with continued use, whereas one that signals while avoiding heavy desensitization may keep working longer.