Long-term inactivation mediated by different FGF-A homologues on heterologously expressed Na1.2 currents
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Lorenzo-Ceballos et al. show that long-term inactivation (LTI) of Na1.2 channels mediated by A-isoforms of different FGF homologues (FGF11–FGF14) differ both in intrinsic rates of onset and rates of recovery from LTI. Furthermore, FGF’s allosterically mediate slowing of fast inactivation. Specific effects of each FGF-A result in homologue-specific use-dependent changes in Naavailability. teaser A-isoforms of cytosolic growth factor homologous factors (FGF11–14) mediate long-term inactivation (LTI) of voltage-dependent sodium (Na) channels. LTI is a rapid onset process that is competitive with the fast inactivation (I) intrinsic to Nachannels, with little or no interconversion between inactivated states. Since recovery from LTI is orders of magnitude slower than recovery from I, repetitive depolarizations lead to use-dependent accumulation of Nachannels in slow recovery states, thereby limiting Naavailability 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 hNa1.2. We also use Nachannels with fast inact
Abstract
Lorenzo-Ceballos et al. show that long-term inactivation (LTI) of Na1.2 channels mediated by A-isoforms of different FGF homologues (FGF11–FGF14) differ both in intrinsic rates of onset and rates of recovery from LTI. Furthermore, FGF’s allosterically mediate slowing of fast inactivation. Specific effects of each FGF-A result in homologue-specific use-dependent changes in Naavailability. teaser A-isoforms of cytosolic growth factor homologous factors (FGF11–14) mediate long-term inactivation (LTI) of voltage-dependent sodium (Na) channels. LTI is a rapid onset process that is competitive with the fast inactivation (I) intrinsic to Nachannels, with little or no interconversion between inactivated states. Since recovery from LTI is orders of magnitude slower than recovery from I, repetitive depolarizations lead to use-dependent accumulation of Nachannels in slow recovery states, thereby limiting Naavailability 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 hNa1.2. We also use Nachannels 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 Na1.2 or with Na1.2_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 Na1.2 channels into LTI. This, in turn, would differentially impact on Naavailability during repetitive firing.