Cellular response

FIGURE 1.5 Schematic diagram of response production by an agonist. An initial stimulus is produced at the receptor as a result of agonist-receptor interaction. This stimulus is processed by the stimulus-response apparatus of the cell into observable cellular response. 

It is amazing to note that complex processes such as drug binding to protein, activation of cells, and observation of syncytial cellular response should apparently so closely follow a model based on these simple concepts. This was not lost on A. J. Clark in his treatise on drug receptor theory The Mode of Action of Drugs on Cells [4] ... 

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. 

It is emphasized that drug activity is observed through a translation process controlled by cells. The aim of pharmacology is to derive system-independent constants characterizing drug activity from the indirect product of cellular response. 

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

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... 

FIGURE 5.3 Different types of functional readouts of agonism. Receptors need not mediate cellular response but may demonstrate behaviors such as internalization into the cytoplasm of the cell (mechanism 1). Receptors can also interact with membrane proteins such as G-proteins (mechanism 2) and produce cytosolic messenger molecules (mechanism 3), which can go on to mediate gene expression (mechanism 4). Receptors can also mediate changes in cellular metabolism (mechanism 5). 

Another potential complication can occur if the responsiveness of the receptor system changes temporally. This can happen if the receptor (or host system, or both) demonstrates desensitization (tachyphylaxis) to drug stimulation (see Chapter 2). There are numerous systems where constant stimulation with a drug does not lead to a constant steady-state response. Rather, a fade of the response occurs. This can be due to depletion of a cofactor in the system producing the cellular response or a conformational change in the receptor protein. Such phenomena protect against overactive stimulation of... 

The observation of dependent variable values (in functional experiments this is cellular response) as they happen (i.e., as the agonist or antagonist binds to the receptor and as the cell responds) is referred to as real time. In contrast, a response chosen at a single point in time is referred to as stop-time experimentation. There are certain experimental formats that must utilize stop-time measurement of responses since the preparation is irreparably altered by the process of measuring response. For example, measurement of gene activation through reporter molecules necessitates lysis of the cell. Therefore, only one... 

Coupling, processes that cause the interaction of molecules with membrane receptors to produce an observable cellular response see Chapter 2.2. 

AKAPs are a diverse family of about 75 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins to cellular compartments and thereby limit and integrate cellular signalling processes at specific sites. This compartmentalization of signalling by AKAPs contributes to the specificity of a cellular response to a given external stimulus (e.g. a particular hormone or neurotransmitter). 

Downregulation is the process that leads to a diminished cellular response. It can involve mechanisms at various levels. 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

Cellular responses to SIP and LPA can be classified as growth-related (stimulation of cell proliferation and... 

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