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Contenido archivado el 2022-12-23

Oscillations in whole-cell receptor binding of opioids and opioid -peptides

Objetivo



This project aims at identifying and investigating the molecular mechanism leading to periodic and chaotic oscillations in the time course of opiate binding with whole cells. These biological periodic phenomena were recently discovered for delta-opiate agonist binding with neuroblastoms X glioma (NGl08-15) hybrid cells.

Besides constituting a novel class of dynamically unstable biological phenomena worthy of investigation in its own right, fluctuations in agonist binding to these popular models of neuronal function are important in advancing understanding of how drugs work - also at different levels of organisation. Oscillations appear to be Nature's unique way of sampling the local environment, and are held fundamental to biological responses ranging from pulsating glycolytic cycles to co-ordinated light emission by groups of fireflies. Oscillations at the single cell level will be generally repeated in tissues and organs, as evidenced by the existence of dynamic instability in nerve cell firing and brain rhythms (EEG) - a specific prediction of fractal theory.

The intracellular source or motor of the oscillations will be identified by employing toxins and other selected inhibitors and effectors to evaluate the participation of various dynamic structural and biochemical elements (some of which are already implicated by preliminary experiments): the microtubule and microfilament cytoskeletons; the receptor-G-protein-mediated signal transduction cascade; phosphoinositide turnover; ion mobilisation; energy pools; membrane properties; etc. Once located, the source will be examined by additional inhibitor/effector experiments in combination with real-time kinetic measurements of the molecular-level events held responsible, e.g. determination of single- or whole-cell Ca2+, Na+, and H+ currents, membrane potential, cytoskeleton alterations, and so forth. Mathematical simulation based on existing intracellular cycles with known feedback capabilities as well as de novo models will be used to clarify possible molecular mechanisms. Ultimately such research will lead to a better understanding of drug action, and possibly of narcotic addiction which has become a worldwide social blight.

Convocatoria de propuestas

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Régimen de financiación

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Coordinador

Medical Research Council (MRC)
Aportación de la UE
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Dirección
20 Park Crescent
W1N 4AL London
Reino Unido

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Participantes (3)