Regulation of Receptors

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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 signaling outputs.

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 drug is diminished. This phenomenon, called tachyphylaxis, occurs rapidly and is important therapeutically; an example is attenuated response to the repeated use of b receptor agonists as bronchodilators for the treatment of asthma (see Chapters 10 and 27).

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. Phosphorylation of agonist-occupied GPCRs by GRKs facilitates the binding of cytosolic proteins termed arrestins to the receptor, resulting in the uncoupling of

G protein from the receptor. The j-arrestins recruit proteins such as PDE4 (which limits cyclic AMP signaling), and others such as clathrin and ji2-adaptin, promoting sequestration of receptor from the membrane (internalization) and providing a scaffold that permits additional signaling steps.

Predictably, supersensitivity to agonists also frequently follows chronic reduction of receptor stimulation. Such situations can result, for example, following withdrawal from prolonged receptor blockade (e.g., the long-term administration of j receptor antagonists such as propranolol (see Chapter 10) or in the case where chronic denervation of a preganglionic fiber induces an increase in neurotransmitter release per pulse, indicating postganglionic neuronal supersensitivity. 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.

DISEASES RESULTING FROM RECEPTOR MALFUNCTION Alteration in receptors and their immediate signaling effectors can be the cause of disease. The loss of a receptor in a highly specialized signaling system may cause a relatively limited, if dramatic, phenotypic disorder (e.g., deficiency of the androgen receptor and androgen insensitivity syndrome; see Chapter 58). Deficiencies in widely employed signaling pathways have broad effects, as are seen in myasthenia gravis and some forms of insulin-resistant diabetes mellitus, which result from autoimmune depletion of nicotinic cholinergic receptors (see Chapter 9) or insulin receptors (see Chapter 60), respectively.

The expression of aberrant or ectopic receptors, effectors, or coupling proteins potentially can lead to supersensitivity, subsensitivity, or other untoward responses. Among the most significant events is the appearance of aberrant receptors as products of oncogenes that transform otherwise normal cells into malignant cells. Virtually any type of signaling system may have oncogenic potential (Chapter 51).

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