Stimulus-response mechanisms

There are numerous second messenger systems such as those utilizing cyclic AMP and cyclic GMP, calcium and calmodulin, phosphoinosiddes, and diacylglerol with accompanying modulatory mechanisms. Each receptor is coupled to these in a variety of ways in different cell types. Therefore, it can be seen that it is impractical to attempt to quantitatively define each stimulus-response mechanism for each receptor system. Fortunately, this is not an... 

The ability to reduce stimulus-response mechanisms to single mono tonic functions allows relative cellular response to yield receptor-specific drug parameters. 

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. 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

In terms of classical receptor theory—where response is a hyperbolic function of stimulus (Response = Stimulus/ (Stimulus 4- [3), [3 is a transducer function reflecting the efficiency of the stimulus-response mechanism of the system), and stimulus is given by Stimulus = [A] e/([A] + KA) (e is the efficacy of the agonist)— Response is given by... 

Stimulus-response coupling, 30—31 Stimulus-response mechanism biochemical nature of, 23-25 definition of, 9... 

The stimulus-response mechanisms in platelets are complex and involve foe variety of substances that stimulate different effector-systems in foe platelets, foe autocrine stimulation in response to platelet activation by a primary agonist as well as by cross-tall between signal transduction pathways. Cross-talk can happen at several stages of foe signal transduction pathway. The most studied are foe competition between stimulatory and inhibitory pathways, and examples are foe action of thrombin via G and PGIj via G,... 

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