Differentiating the contributions of Na+/K+ pump current and persistent Na+ current in simulated voltage-clamp experiments.

The persistent Na⁺ current (I_NaP) is thought to play important roles in many brain regions including the generation of inspiration in the ventral respiratory column (VRC) of mammals. The characterization of the slow inactivation of I_NaP requires long-lasting voltage steps (>1 s), which will increase intracellular Na⁺ and activate the Na⁺/K⁺-ATPase pump current (I_Pump). Thus, I_Pump may contribute to the previously measured slow inactivation of I_NaP and the generation of the inspiratory bursting rhythm. To test this hypothesis, we computationally modeled a respiratory pacemaker neuron that included a noninactivating I_NaP and I_Pump in addition to other basic spike-generating currents. This model produces an inspiration-like bursting rhythm, in which the dynamics of [Na⁺]_i account for burst initiation and termination. We simulated a voltage-clamp experiment measuring the I_NaP inactivation kinetics using our model of noninactivating I_NaP and I_Pump. Consistent with prior measurements in the VRC, we found a sigmoidal inactivation curve and a current that only partially inactivated reaching a minimum inactivation of 0.37. The biexponential time course of inactivation had decay rate constants of 0.45 s and 2.33 s with contributions of 49% and 51%, respectively. The time constant of inactivation was 2.16 s. This decay was caused by the slow growth of I_Pump and the slow hyperpolarization of the Na⁺ reversal potential in response to the growing [Na⁺]_i. We conclude that important biophysical properties previously attributed to the I_NaP may be caused by I_Pump. This has important implications for understanding respiratory rhythmogenesis and other neuronal functions.NEW & NOTEWORTHY The slow inactivation of the persistent Na⁺ current has been implicated in numerous neuronal functions. Our computational approach indicates that voltage-clamp experiments may show a slow inactivation that is actually caused by the Na⁺/K⁺ pump current and a changing Na⁺ reversal potential rather than a slow Na⁺ inactivation process. These results call into question to what extent the slow inactivation of the persistent Na⁺ current is solely important for neuronal functions.