Receptor occupancy

The dissociation content for the competitive antagonist, iCg, can be deterrnined without knowing the relationship between receptor occupancy and response. Equation 17 is often written in logarithmic form ... 

FIGURE 2.2 Binding and dose-response curves for human calcitonin on human calcitonin receptors type 2. (a) Dose-response curves for microphysiometry responses to human calcitonin in HEK cells (open circles) and binding in membranes from HEK cells (displacement of [,25I]-human calcitonin). Data from [1]. (b) Regression of microphysiometry responses to human calcitonin (ordinates) upon human calcitonin fractional receptor occupancy (abscissae). Dotted line shows a direct correlation between receptor occupancy and cellular response. 

Receptor reserve is a property of the tissue (i.e., the strength of amplification of receptor stimulus inherent to the cells) and it is a property of the agonist (i.e., how much stimulus is imparted to the system by a given agonist receptor occupancy). This latter factor is quantified as the efficacy of the agonist. A high-efficacy agonist need occupy a smaller fraction of the receptor population than a... 

FIGURE 2.11 Receptor-occupancy curves for activation of human calcitonin type 2 receptors by the agonist human calcitonin. Ordinates (response as a fraction of the maximal response to human calcitonin). Abscissae (fractional receptor occupancy by human calcitonin). Curves shown for receptors transfected into three cell types human embryonic kidney cells (HEK), Chinese hamster ovary cells (CHO), and Xenopus laevis melanophores. It can be seen that the different cell types lead to differing amplification factors for the conversion from agonist receptor occupancy to tissue response. 

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

Different drugs have different inherent capacities to induce response (intrinsic efficacy). Thus, equal cellular responses can be achieved by different fractional receptor occupancies of these drugs. 

The function f is usually hyperbolic, which introduces the nonlinearity between receptor occupancy and response. A common experimentally observed relationship between receptor stimulus and response is a rectangular hyperbola (see Chapter 2). Thus, response can be thought of as a hyperbolic function of stimulus ... 

The various components of classical theory relating receptor occupancy to tissue response are shown schematically in Figure 3.5. It will be seen that this formally is identical to the equation for response derived in the operational model (see material following), where x = [Rt]e/p. 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

FIGURE 3.7 Principal components of the operational model. The 3D array defines processes of receptor occupation (plane 1), the transduction of the agonist occupancy into response (plane 2) in defining the relationship between agonist concentration, and tissue response (plane 3). The term a refers to the intrinsic activity of the agonist. 

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

Weiss, J. M., Morgan, P. H., Lutz, M. W., and Kenakin, T. P. (1996a). The cubic ternary complex receptor-occupancy model. I. Model description. J. Theroet. Biol. 178 151-167. 

FIGURE 4.13 Effect of the allosteric modulator 5-(N-ethyl-N-isopropyl)-amyloride (EPA) on the kinetics dissociation of [3H] yohimbine from c/j-adrenoceptors, (a) Receptor occupancy of [3H] yohimbine with time in the absence (filled circles) and presence (open circles) of EPA 0.03 mM, 0.1 mM (filled triangles), 0.3 mM (open squares), 1 mM (filled squares), and 3 mM (open triangles), (b) Regression of observed rate constant for offset of concentration of [3H] yohimbine in the presence of various concentrations of EPA on concentrations of EPA (abscissae in mM on a logarithmic scale). Data redrawn from [13]. 

Ehlert, F. J. (1985). The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium. Mol. Pharmacol. 28 410-421. 

The kinetic equation for the adjustment of receptor occupancy (pt) by a preequilibrated concentration of an... 

The receptor occupancy curve can be converted to concentration-response curves by processing occupancy through the operational model for agonism (see Section 3.6). Under these circumstances, Equation 6.6 becomes... 

This is formally identical to the equation derived by Gaddum and colleagues [3] (see Section 6.8.2) for noncompetitive antagonism. In this case, it is assumed that the only available receptor population in the presence of a fractional receptor occupancy pB by a noncompetitive antagonist is the fraction l-pB. Thus, agonist receptor occupancy is given by... 

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