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Modeling of Single Noninactivating Na⁺ Channels: Evidence for Two Open and Several Fast Inactivated States

Yu-Kai The ^* , Jacqueline Fernandes , M. Oana Popa , Alexi K. Alekov , Jens Timmer ^*  and Holger Lerche 

^* Institut für Physik, and Freiburger Zentrum für Datenanalyse und Modellbildung, Universität Freiburg, Freiburg, Germany; and Neurologische Klinik und Abteilung für Angewandte Physiologie, Universität Ulm, Ulm, Germany

Correspondence: Address reprint requests to Holger Lerche, E-mail: holger.lerche{at}uni-ulm.de.

Voltage-gated Na⁺ channels play a fundamental role in the excitability of nerve and muscle cells. Defects in fast Na⁺ channel inactivation can cause hereditary muscle diseases with hyper- or hypoexcitability of the sarcolemma. To explore the kinetics and gating mechanisms of noninactivating muscle Na⁺ channels on a molecular level, we analyzed single channel currents from wild-type and five mutant Na⁺ channels. The mutations were localized in different protein regions which have been previously shown to be important for fast inactivation (D3-D4-linker, D3/S4-S5, D4/S4-S5, D4/S6) and exhibited distinct grades of defective fast inactivation with varying levels of persistent Na⁺ currents caused by late channel reopenings. Different gating schemes were fitted to the data using hidden Markov models with a correction for time interval omission and compared statistically. For all investigated channels including the wild-type, two open states were necessary to describe our data. Whereas one inactivated state was sufficient to fit the single channel behavior of wild-type channels, modeling the mutants with impaired fast inactivation revealed evidence for several inactivated states. We propose a single gating scheme with two open and three inactivated states to describe the behavior of all five examined mutants. This scheme provides a biological interpretation of the collected data, based on previous investigations in voltage-gated Na⁺ and K⁺ channels.