Some Characteristics of Receptors

A. Spare receptors

A characteristic of many receptors, particularly those that respond to hormones, neurotransmitters, and peptides, is their ability to amplify signal duration and intensity. The family of G protein–linked receptors exemplifies many of the possible responses initiated by ligand binding to a receptor. Specifically, two phenomena account for the amplification of the ligandreceptor signal. First, a single ligand–receptor complex can interact with many G proteins, thereby multiplying the original signal many-fold. Second, the activated G proteins persist for a longer duration than the original ligand–receptor complex. The binding of albuterol, for example, may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Further prolongation and amplification of the initial signal is mediated by the interaction between G proteins and their respective intracellular targets.

Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell. Systems that exhibit this behavior are said to have spare receptors. Spare receptors are exhibited by insulin receptors, where it has been estimated that 99 percent of the receptors are “spare.” This constitutes an immense functional reserve that ensures adequate amounts of glucose enter the cell. On the other end of the scale is the human heart, in which about five to ten percent of the total β-adrenoceptors are spare. An important implication of this observation is that little functional reserve exists in the failing heart; most receptors must be occupied to obtain maximum contractility

Figure 2.5 Desensitization of receptors. 

B. Desensitization of receptors 

Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor. To prevent potential damage to the cell (for example, high concentrations of calcium, initiating cell death), several mechanisms have evolved to protect a cell from excessive stimulation. When repeated administration of a drug results in a diminished effect, the phenomenon is called tachyphylaxis. The receptor becomes desensitized to the action of the drug

Figure  Desensitization of receptors.

 In this phenomenon, the receptors are still present on the cell surface but are unresponsive to the ligand. Other types of desensitization occur when receptors are down-regulated. Binding of the agonist results in molecular changes in the membrane-bound receptors, such that the receptor undergoes endocytosis and is sequestered from further agonist interaction. These receptors may be recycled to the cell surface, restoring sensitivity, or alternatively, may be further processed and degraded, decreasing the total number of receptors available. Some receptors, particularly voltagegated channels, require a finite time (rest period) following stimulation before they can be activated again. During this recovery phase they are said to be “refractory” or “unresponsive.”

 C. Importance of the receptor concept

It is important that we understand the roles and functions of receptors because most drugs interact with receptors that will determine selective therapeutic and toxic effects of the drug. Moreover, receptors largely determine the quantitative relations between dose of a drug and pharmacologic effect.