In this proposal we seek continued support for our efforts to characterize the physiological mechanisms involved in control of the electrically excitable sodium channel. Using axial wire voltage clamp in crayfish giant axons and patch clamp methods in cultured neuroblastoma cells, we seek further clarification with respect to the following major questions: (a) what is the nature of the interaction between the """"""""immobilizable"""""""" and """"""""nonimmobilizable"""""""" components of gating charge? (b) to what extent can the observed properties of these gating current components be correlated with: i. the behavior of the kinetic components which we have characterized within the sodium ionic currents; and, ii. the concept that fast and slow inactivation represent separate and parallel processes? Answers will be sought through sophisticated kinetic analysis of both gating and ionic currents, in addition to using a wide range of pharmacological agents to modify normal axon behavior. Results will be used to generate a rigorous biophysical model which can then be used to predict additional, experimentally testable, aspects of axon excitability. This work takes on added urgency in view of the very rapid progress not being made by the biochemical approaches to sodium channel structure. This work is of substantial health-related significance and is expected to add to our basic understanding of neural excitability in man. Results of this work will contribute to the understanding of all systems in which electrically excitable sodium channels are involved, including: the cardiovascular system, as well as the central, peripheral and autonomic nervous system. Finally this work may well help in the design of new or safer local anesthetic and antiarrhythmic drugs.
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