Receptors are dynamically regulated in number, location, and interaction with other molecules. Changes can occur over short times (minutes) and longer periods (days).
Frequent or continuous exposure to agonists often results in short-term diminution of the receptor response, sometimes called tachyphylaxis. Several mechanisms are responsible for this phenomenon.
First, intracellular molecules may block access of a G protein to the activated receptor molecule. For example, the molecule β-arrestin has been shown to bind to an intracellular loop of the β adrenoceptor when the receptor is continuously activated. Beta-arrestin prevents access of the Gs-coupling protein and thus desensitizes the tissue to further β-agonist activation within minutes. Removal of the β agonist results in removal of β-arrestin and restoration of the full response after a few minutes or hours.
Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules. The internalized receptor molecule may then be either reinserted into the membrane (eg, morphine receptors) or degraded (eg, β adrenoceptors, epidermal growth factor receptors). In some cases, a cyclic internalization-reinsertion process may actually be necessary for normal functioning of the receptor-effector system.
Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects. For example, depletion of thiol cofactors may be responsible for tolerance to nitroglycerin. In some cases, repletion of the missing substrate (eg, by administration of glutathione) can reverse the tolerance.
Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation.