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Percent Change in Receptor Number

FIGURE 10 The effects of up- or down-regulation of receptor number on sensitivity to hormonal stimulation.

of hormone will encounter a molecule of receptor. If there are no hormones or no receptors, there can be no response. The higher the concentration of hormone, the more likely it is to interact with its receptors. Similarly, the more receptors available to interact with any particular concentration of hormone, the greater the likelihood of a response. In other words, the probability that a molecule of hormone will encounter a molecule of receptor is related to the abundance of both the hormone and the receptor. The effects of changing receptor abundance on hormone sensitivity are shown in Fig. 10. Note that the relationship is not linear, and that increasing the receptor number by 40% decreases the hormone concentration needed to produce a halfmaximal response by almost a factor of 2, while decreasing the number of receptors by 40% increases the needed concentration of hormone by a factor of 5. Down-regulation is frequently encountered and may result from inactivation of receptors by covalent modification, from an increased rate of sequestration of internalized membrane receptors, or from a change in the rates of receptor degradation or synthesis.

The other determinant of sensitivity is the affinity of the receptor for the hormone. Affinity reflects the ''tightness'' of binding or the likelihood that an encounter between a hormone and its receptor will result in binding. Affinity is usually defined in terms of the concentration of hormone needed to occupy half of the available receptors. Although the affinity of a receptor for its hormone may be adjusted by covalent modifications such as phosphorylation or dephosphor-ylation, in general, it appears the number of receptors is regulated rather than their affinity.

Biological responses do not necessarily parallel hormone binding and, therefore, are not limited by the affinity of the receptor for the hormone. Because they depend on many postreceptor events, responses to some hormones may be at a maximum at concentrations of hormone that do not saturate all of the receptors (Fig. 11). When fewer than 100% of the receptors need to be occupied to obtain a maximum response, cells are said to express spare receptors. For example, glucose uptake by fat cells is stimulated by insulin in a dose-dependent manner, but the response reaches a maximum when only a small percent of available receptors are occupied by insulin. Consequently, a half-maximal response to insulin is achieved at a concentration that is considerably lower than that required to occupy half of the receptors and, hence, the sensitivity of the cell is considerably greater than the affinity of the receptor. Recall that sensitivity is measured in terms of a biological response, which is the physiologically meaningful parameter, whereas affinity is independent of the postreceptor events that produce the biological response. The magnitude of a cellular response to a hormone is determined by the summation of the signal generated by each of the occupied receptors, and therefore is related to the number of receptors that are activated rather than the fraction of the total receptor pool that is bound to hormone. However, because the

Hormone Binding

Hormone Binding

Hormone Concentration (ng/ml) FIGURE 11 Spare receptors. Note that the concentration of hormone needed to produce a half-maximal response is considerably lower than that needed to occupy half of the receptors.

percentage of available receptors that bind to hormone is determined by the hormone concentration, the number of activated receptors needed to a produce a halfmaximal response will be equivalent to a smaller and smaller fraction as the total number of receptors increases. In the example shown in Fig. 11 expression of five times more receptors than needed for a maximum response increases the sensitivity sevenfold.

Another consequence of spare membrane receptors relates to the rapidity with which hormone can be cleared from the blood. Degradation of peptide hormones depends in part on receptor-mediated internalization of the hormone and hence access to degrading enzymes. Some membrane receptors such as the C-type receptors for the atrial natriuretic hormone (see Chapter 29) lack the biochemical components needed for signal transduction, and have a role only in hormone degradation. Spare receptors thus may blunt potentially harmful overresponses to rapid changes in peptide hormone concentrations.

Sensitivity to hormonal stimulation can also be modulated in ways that do not involve changes in receptor number or affinity. Postreceptor modulation may affect any of the steps in the biological pathway through which hormonal effects are produced. Up- or down-regulation of effector molecules such as enzymes, ion channels, and contractile proteins may amplify or dampen responses and, hence, change the relationship between receptor occupancy and magnitude of response. For example, the activity of cAMP phosphodiesterase increases in adipocytes in the absence of pituitary hormones. Recall from Chapter 2 that this enzyme catalyzes the degradation of cAMP, and when its activity is increased, less cAMP can accumulate after stimulation of adenylyl cyclase by a hormone such as epinephrine. Therefore, if all other things were equal, a higher concentration of epinephrine would be needed to produce a given amount of lipolysis than might be necessary in the presence of normal amounts of pituitary hormones; hence, sensitivity to epinephrine appears reduced.

At the tissue, organ, or whole-body level, the response to a hormone is the aggregate of the contributions of all of the stimulated cells, so that the magnitude of the response is determined both by the number of responsive cells and their competence. For example, the pituitary hormone ACTH stimulates the adrenal glands to secrete their hormone, cortisol, in a dose-related manner. However, immediately after removal of one adrenal gland, changes in the concentration of cortisol in response to ACTH administration would be only half as large as seen when both glands are present. Therefore, a much higher dose of ACTH will be needed to achieve the same change as was produced preoperatively.

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