Regulation of Receptors
Receptors are themselves subject to physiological regulation. The number of receptors a cell has (or the affinity of the receptors for their specific messenger) can be increased or decreased, at least in certain systems.
A single cell contains between 500 and 100,000 receptors on the surface of its cell membrane, with additional receptors in the cytosol and nucleus. In any given cell, the number of receptors may change over time. Old receptors are withdrawn from the membrane by endocytosis and are broken down in lysosomes. New receptors are inserted into the membrane by exocytosis. Intracellular receptors are also made and broken down. This flexibility permits a cell to vary its reponses to chemical signals depending on the extracellular conditions and the internal needs of the cell.
This refers to a decrease in the total number of target-cell receptors for a given messenger in response to chronic high extracellular concentration of the messenger. Down-regulation is an important example of receptor regulation. When a high extracellular concentration of a messenger is maintained for some time, the total number of the target cell’s receptors for that messenger may decrease (that is, down-regulate). Down regulation has the effect of reducing the target cells’ responsiveness to frequent or intense stimulation by a messenger (that is, desensitizing them) and thus represents a local negative feedback mechanism.
Down-regulation takes two forms: either a decrease in receptor number or a decrease in binding affinity. The cell can physically withdraw receptors from the membrane through endocytosis. A quicker and more easily reversible type of down-regulation, called desensitization, can be achieved by binding a chemical modulator to the receptor protein. For example, the β-adrenergic receptors can be desensitized by phosphorylation of the receptor. The result of reduced receptor number or decreased binding affinity is a diminished response of the target cell even though the concentration of the signal molecule remains high.
Change in the opposite direction (up-regulation) also occurs.
An increase in the total number of target-cell receptors for a given messenger in response to a chronic low extracellular concentration of the messenger
Cells exposed to for a prolonged period to very low concentrations of a messenger may come to have many more receptors for that messenger, thereby developing increased sensitivity (hypersensitivity) to it. For example, days after the nerves to a muscle are cut, thereby eliminating the delivery of neurotransmitter from those nerves, the muscle will contract in response to much smaller amounts of experimentally injected neurotransmitter than that to which a normal muscle responds.
If the concentration of a ligand decreases, the target cell may use up-regulation to insert more receptors into the cell membrane in an attempt to keep its response at a normal level. For example, if a nerve cell is damaged and unable to release normal amounts of neurotransmitter, its target cell will up-regulate its receptors. This up-regulation makes the target cell more sensitive to whatever neurotransmitters are present.
Up-regulation and down-regulation are made possible because there is a continuous degradation and synthesis of receptors. The main cause of down-regulation of plasma-membrane receptors is as follows:
The binding of a messenger to its receptor can stimulate the internalization or f the complex; that is, the messenger-receptor complex is taken into the cell by endocytosis (an example of so-called receptor-mediated endocytosis). This increases the rate of receptor degradation inside the cell. Thus, at high hormone concentrations, the number of plasma-membrane receptors of that type gradually decreases during down-regulation.
The opposite event also occur and contribute to up-regulation. The cell may contain stores of receptors in the membrane of intracellular vesicles; these are then inserted into the membrane through exocytosis during up-regulation.
Another important mechanism of up-regulation and down-regulation is alteration of the expression of the genes that code for the receptors.
Down-regulation and up-regulation are physiological processes in which the number of receptors or their affinity for messenger becomes abnormal. The result is unusually large or small responses to any given level of messenger. For example, the disease called myasthenia gravis is due to the destruction of the skeletal muscle receptors for acetylcholine, the neurotransmitter that normally causes contraction of the muscle in response to nerve stimulation. The result is muscle weakness or paralysis.
Receptor Down-Regulation and Drug Tolerance
Down-regulation is one of the explanations for the development of drug tolerance, a condition in which the response to a given dose decreases despite continuous exposure to the drug. The development of tolerance to opiates, such as morphine and codeine, occurs when the receptors for these drugs down-regulate.