Receptor density

The number of functioning receptors controls the magnitude of the initial stimulus given to the cell by an agonist. Number of receptors on the cell surface is one means the cell can control its stimulatory environment. Thus, it is not surprising that receptor density varies with different cell types. Potentially, this can be used to control... 

From this equation it can be seen that for a given receptor density systems can spontaneously produce physiological response and that this response is facilitated by high G-protein concentration, high-affinity receptor/ G-protein coupling (low value of KG), and/or a natural tendency for the receptor to spontaneously form the active state. This latter property is described by the magnitude of L, a thermodynamic constant unique for every receptor. 

There is a capability to alter the receptor density (or cells available with a range of receptor densities). 

The first idea to consider is the effect of receptor density on sensitivity of a functional system to agonists. Clearly, if quanta of stimulus are delivered to the stimulus-response mechanism of a cell per activated receptor the amount of the total stimulus will be directly proportional to the number of receptors activated. Figure 5.8 shows Gi-protein-mediated responses of melanophores transiently transfected with cDNA for human neuropeptide Y-l receptors. As can be seen from this figure, increasing receptor expression (transfection with increasing concentrations of receptor cDNA) causes an increased potency and maximal response to the neuropeptide Y agonist PYY. 

Receptor density has disparate effects on the potency and maximal responses to agonists. The operational model predicts that the EC50 to an agonist will vary with receptor density according to the following relationship (see Section 3.13.3)... 

The maximal response in the presence of antagonist is given by (1 + x)/(l + z + [B]/Kb). It can be seen that for low values of z (low efficacy agonist and/or low receptor density or poor receptor coupling) the maximal response to the agonist will be <1. 

Here it can be seen that for very efficacious agonists, or in systems of high receptor density or very efficient receptor coupling (all leading to high values of t), the maximal... 

FIGURE 7.14 Effect of an allosteric modulator that increases the efficacy of the agonist but has no effect on affinity in two different systems, (a) For full agonists, increases in efficacy produce parallel shifts to the left of the concentration-response curves. Responses modeled with Equation 7.3 with a= 1, , = 5, t = 20, and Ka = 3j.lM. Curves shown for [B]/Kb = 0, 0.3, 1, 3, 10, and 30. (b) In systems with lower receptor density and/or poorer receptor coupling where the agonists does not produce the full system maximal response, an allosteric modulator increases the maximal response and shifts the curves to the left. Responses modeled with Equation 7.3 for the same agonist and same allosteric modulator but in a different tissue (parameters as for A except t= 1). 

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