Receptor interactions, determination mechanism

Fig. 10. Hypothesis for the interaction of the A-kinase (A-K) system activated by ACTH with the C-kinase system (C-K) in the long-term regulation of the enzymes of steroidogenesis throughout the adrenal cortex. The primary determinant of zonation of A-kinase and C-kinase activities, via zonation of cell surface receptors or other mechanisms, is hypothesized to be a gradient (e.g., of steroids) created by the pattern of blood flow in the adrenal cortex. The resultant levels of induction of steroidogenic enzymes are indicated by to show particular elevation and by to show particular lack of induction or suppression of induction. Other enzymes involved in steroidogenesis are shown in parentheses. SCC=cholesterol side-chain cleavage enzyme 3/3=3/3-hydroxysteroid dehydrogenase 17a=17a-hy-droxylase 21 =21-hydroxylase 11/3= 11/3-hydroxylase CMO= corticosterone methyl oxidase activity of 11/3-hydroxylase. Secreted steroids are indicated as B=corticosterone Aldo=aldosterone F=cortisol DHEA(S)= dehydroepiandrosterone (sulfate).

The suprahypothalamic neurotransmitter level can be assessed by a determination of catecholamines in circumscribed brain areas, the technique requires preparation of frozen tissue and isolation of specific nuclei by the micropunch technique. The catecholamines and indolamines can be measured by a radio-enzymatic methods and by a high-pressure liquid chromatography (HPLC) with electrochemical detection. These mechanistic investigations are mostly initiated due to questions arising from the receptor interaction profile of the drug candidate, they may be required to prove that such receptor interactions truly change the functional state of neurotransmitters (functional expression). Mostly, however, the peripheral effects of such neurotransmitter mechanisms (for instance prolactin secretion) are sufficiently distinct. 

Most olfaction models in the literature are far too simplistic and too mechanical in nature, and none of them have succeeded in accounting for all of the observations about olfaction. As described, recent advances in our understanding have confirmed that odor perception, as predicted by Polak (19), starts with a combinatorial mechanism at the receptor level (1) and involves pattern recognition in the higher brain (4). No single odorant-receptor interaction will be the sole determinant of odor percept, and even knowledge of the pattern elicited at the olfactory bulb is insufficient to enable prediction of the cortical image of odor. Therefore, structure/odor models are and, for the foreseeable future, will remain statistical tools rather than mechanistic indicators. 

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