Topic 2: Reading: Receptor regulation

Receptors not only initiate regulation of biochemical events and physiological function but also are themselves subject to many regulatory and homeostatic controls. These controls include regulation of the synthesis and degradation of the receptor by multiple mechanisms, covalent modification, association with other regulatory proteins, and/or relocalization within the cell. Transducer and effector proteins are regulated similarly. Modulating inputs may come from other receptors, directly or indirectly, and receptors are almost always subject to feedback regulation by their own signalling outputs. The variation in therapeutic response of a drug could be due to the following mechanisms.

Down-regulation of receptors: Continued stimulation of cells with agonists generally results in a state of desensitization (also referred to as adaptation, refractoriness, or down-regulation) such that the effect that follows continued or subsequent exposure to the same concentration of a drug is diminished. This phenomenon, called tachyphylaxis, occurs rapidly and is important therapeutically. Example: Repeated use of beta-receptor agonists as bronchodilators for the treatment of asthma. The dose of beta-receptor agonist needs to be increased for getting the same therapeutic response as during the initial period of treatment.

Desensitization can result from temporary inaccessibility of the receptor to agonist or from fewer receptors synthesized and available at the cell surface (e.g., down-regulation of receptor number). Phosphorylation of the receptor by specific GPCR kinases (GRKs) plays a key role in triggering rapid desensitization.

Up-regulation of receptors: Supersensitivity to agonists also frequently follows the chronic reduction of receptor stimulation. Supersensitivity usually due to the up-regulation of receptors at the cell surface. Such situations can result, for example, following withdrawal from prolonged receptor blockade (e.g., the long-term administration of beta- receptor antagonists such as propranolol. Abrupt cessation of propranolol therapy can lead to a sudden increase in the heart rate and blood pressure. Supersensitivity can be the result of tissue response to pathological conditions, such as it happens in cardiac ischemia and is due to synthesis and recruitment of new receptors to the surface of the myocyte.