Intracellular Calcium Alters Sodium Channel Kinetics To Influence Neuronal Firing

Intracellular calcium can modulate the kinetics of voltage-gated sodium (Nav) and other channels. Existing studies on Nav channels report effects on intrinsic kinetic properties, including inactivation. Here, we show evidence that calcium may also modulate the interaction between Nav channels and fibroblast growth factor-homologous factors (FHFs). Certain FHF subtypes bind to the C-terminus of Nav channels and result in an open-state block that competes with endogenous fast inactivation. This binding is fast (ms) at depolarizing voltages, but unbinding is very slow (100s of ms). Neurons that express these FHF subtypes have characteristically low firing rates. The calcium-dependent effect that we observe is mostly a change in the kinetics of recovery from the FHF-induced long-term inactivation. This calcium dependence may serve as an additional feedback mechanism for regulating neuronal firing rates.