Long-term inactivation mediated by different FGF-A homologues on heterologously expressed NaV1.2 currents.

Abstract

A-isoforms of cytosolic growth factor homologous factors (FGF11-14) mediate long-term inactivation (LTI) of voltage-dependent sodium (NaV) channels. LTI is a rapid onset process that is competitive with the fast inactivation (IF) intrinsic to NaV channels, with little or no interconversion between inactivated states. Since recovery from LTI is orders of magnitude slower than recovery from IF, repetitive depolarizations lead to use-dependent accumulation of NaV channels in slow recovery states, thereby limiting NaV availability during trains of action potentials. Of the two or more N-terminal splice variants of the various FGF homologues, LTI specifically arises only from the A-isoform of each FGF subunit. Although there is substantial homology among the N termini of the four FGF-A paralogs, to what extent LTI generated by the different FGF-A homologues may differ has not been directly addressed. Here, using heterologous expression in HEK293T cells, we evaluate the kinetics of onset and recovery from LTI mediated by hFGF11-14A in association with WT hNaV1.2. We also use NaV channels with fast inactivation removed (IQM) to measure rates of LTI-mediated inactivation and recovery in the absence of intrinsic fast inactivation. Among the four FGF-A homologues, we identify two features that can differ. First, different FGF-A's differ in the rate of onset into LTI. Second, the rate of recovery from inactivation, whether measured with WT NaV1.2 or with NaV1.2_IQM, differs among FGF-A's. The functional differences among FGF-A homologues differentially sculpt the time course and extent of use-dependent accumulation of NaV1.2 channels into LTI. This, in turn, would differentially impact on NaV availability during repetitive firing.