A comparative analysis of models of Na+ channel gating for mammalian and invertebrate nonmyelinated axons: Relationship to energy efficient action potentials

The rapidly activating, voltage gated Na+ current, INa, has recently been measured in mammalian nonmyelinated axons. Those results have been incorporated in simulations of the action potential, results that demonstrate a significant separation in time during the spike between INa and the repolarizing K+ current, IK. The original Hodgkin and Huxley (1952) model of Na+ channel gating, m3h, where m and h are channel activation and inactivation, respectively, has been used in this analysis. This model was originally developed for invertebrate nonmyelinated axons, squid giant axons in particular. The model has not survived challenges based on results from invertebrate preparations using a double-step voltage clamp protocol and measurements of gating currents, results that demonstrate a kinetic link between activation and inactivation leading to a delayed onset of inactivation following a voltage step. These processes are independent of each other in the Hodgkin and Huxley (1952) model. Application of the double-step protocol to the m3h model for mammalian INa results reveals a surprising prediction, an apparent delay in onset of inactivation even though activation and inactivation are uncoupled in the model. Other results, most notably gating currents, will be required to demonstrate such a link, if indeed it exists for mammalian Na+ channels. The information obtained will be significant in determining the way in which the Na+ channel is sequestered away from its open state during repolarization, thereby allowing for a separation in time between INa and IK during a spike, an energetically efficient mechanism of neuronal signaling in the mammalian brain.