D50 Log Drug nM 1 Consider that drugs A B C and D represent

D50 Log [Drug] nM 1. Consider that drugs A, B, C, and D represent the same agonist drug (meaning they are all drug A) administered to different tissues. In this case, the drugs are all acting on the same receptor (because they are the same drug), but we see different responses in the different tissues. The reason for this variable effect could be: A. Spare receptors B. Tissues with different intrinsic activity C. Receptor recycling D. A & E. All of the above 2. Receptor supersensitivity may be caused by: A. Exposure of the receptor to an antagonist. B. A decrease in receptor number due to hormones. C. Exposure of the receptor to an agonist. D. A & B E. B & C

Solution

1. E

The agonist drug has a different EC₅₀ in different tissues,and we cannot conclude that the receptors in one tissue are different from the receptors in the other tissue, because there is no predictable relationship between EC₅₀ and K_D for a particular agonist/receptor combination. Spare receptors are also responsible for tissue specific actions of agonists.Because the presence of spare receptors increase the potency of an agonist,tissues with a high proportion of spare receptors will respond to agonists at lower concentrations,even if they contain exactly the same receptor subtypes

Spare receptors also complicate the analysis of partial agonists. If a drug is a partial agonist in one tissue, it may be a full agonist in another tissue, which has a higher proportion of spare receptors. In the GPCR example described, where only 10% of the receptors must be activated to cause a full response, a weak partial agonist may activate this 10% and appear to be a full agonist. Because of this problem, a different term, intrinsic activity, is used to describe the ability of a tissue to respond to agonist stimulation. Efficacy, which is the ability of the agonist to cause the receptor to assume an active conformation, is analogous to K_D in that both are constant for a given drug/receptor pair. It is an intrinsic property that depends on the structural complementarity of the drug and the receptor molecules. Intrinsic activity, however, is highly context dependent. It varies in different tissues because of the presence of different proportions of spare receptors and downstream amplification mechanisms. A drug can be a partial agonist in efficacy, but a full agonist in intrinsic activity when spare receptors are present. Receptor cycling also interfere in the drug action ie.,readiness of the drug-receptor complex dissociation results in different response in different tissue.

2. D. A and B

The response of any cell to hormones or neurotransmitters is tightly regulated and can vary depending on other stimuli impinging on the cell. Very often, the number of receptors in the membrane of a cell or responsiveness of the receptors themselves is regulated. One hormone can sensitize a cell to the effects of another hormone, and more commonly, when a cell is continuously exposed to stimulation by a transmitter or hormone, it may become desensitized.

In the absence of hormone, most receptors are not localized to particular regions of the cell membrane. When a hormone binds, receptors rapidly migrate to coated pits. These are specialized invaginations of the membrane surrounded by an electron-dense cage formed by the protein clathrin; this is where receptor-mediated endocytosis occurs. Segments of membranes within coated pits rapidly pinch off to form intracellular vesicles rich in receptor-ligand complexes. Vesicles then fuse with tubular-reticular structures. In most cases dissociated hormone is incorporated into vesicles that fuse with lysosomes, with the hormone then degraded by lysosomal enzymes. Dissociated receptor recirculates to the cell surface. However, a fraction of internalized hormone may also be recirculated to the cell surface along with receptor, and then released. This process is termed retroendocytosis. Free receptors may recirculate to the cell surface or may be sequestered temporarily in an intracellular membrane compartment. Alternatively, receptor may be transported to lysosomes, where it is also degraded. The latter two cases result in a net decrease in cell receptor number.

Finally, it is important to realize that the number of receptors in the plasma membrane of cells is not static. Receptor number may be increased or decreased under the influence of hormonal mechanisms. Altered receptor number attributable to internalization or degradation has an intermediate time course, whereas an altered rate of receptor synthesis occurs more slowly. Receptors may also be up regulated, and this phenomenon can result in receptor supersensitivity. Up regulation can occur after exposure of the receptor to an antagonist, or inhibition of transmitter synthesis or release