Numeric simulations of models for the effect of drugs on voltage-dependent ion channels.

• Grant number: 11/08658-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2011
• End date: August 31, 2012
• Field of knowledge: Biological Sciences - Biophysics
• Principal Investigator: Antonio Carlos Cassola
• Grantee: Andre Lazzeri Cortez
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The states of an ionic channel, closed or resting, open and inactivated, correspond to different conformations of the forming protein. Several chemical compounds whose effects on channels, mostly blockers, are due to a direct action on the protein, bind to a specific site on it. The sites may be modified in the transition between states and its drug binding affinity may change. The phenomenon is well known in the literature as state-dependent blocking. Some local anesthetics, with higher binding affinity for the open state of the Nav channel, have inhibitory effects that are dependent on the frequency of the transitions. This characteristic is the basis for the anti-arrhythmic effects. This laboratory has been dedicated in the last years to the study of compounds with inhibitory effects on ion channels. The project proposed is the numeric simulation of models for drug-channels interaction. Comparison of the simulation with experimental results may provide support for specific hypothesis regarding drug effects on channels. In the simulations of voltage-dependent channels the rate constants for the equilibrium between resting and open state are instantaneously modified with electrical potential difference changes. The relationship between the rate constants and membrane potential is given by Boltzmann type relation. Following a change in membrane potential the relaxation to a new equilibrium condition follows an exponential time course. In the models, the drug binds to one or more channel states. The state probabilities depend on the rate constants for the transition between contiguous conformations. The differential equations for the models will be solved by numeric integrations using the Euler method. The kinetics of the currents in the model will be compared to the real currents. The best fitting of the observed currents qualifies the model for the mechanistic description of the drug-channel interaction.