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Another Piece to the Intracellular FGF/Na+ Channel Puzzle

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Another Piece to the Intracellular FGF/Na+ Channel Puzzle COMMENTARY Another piece to the intracellular FGF/Na+ channel puzzle COMMENTARY Elizabeth J. Akina and Michael M. Tamkuna,1 Neuronal communication requires the propagation of precisely regulated action potentials. Although a myriad of ion channels and modulatory proteins con- tribute to the action potential waveform and firing properties of each neuron, voltage-gated sodium (Nav) channels typically generate the crucial depolar- izing event. Early Nav channel biochemistry identified two beta subunits (1), thus generating excitement over how accessory proteins might be involved in Nav chan- nel physiology. In recent years, Nav channel interactors have grown to include intracellular fibroblast growth factor homologous factors (iFGFs) (for a recent review of this subject, see ref. 2). Although the majority of FGFs are secreted growth factors, a four-member subfamily now designated FGF11-14 is distinguished by generating nonsecreted proteins that do not inter- act with FGF receptors. Pioneering efforts by Waxman and colleagues (3, 4) demonstrated that these non- canonical FGFs directly bind the C terminus of Nav channels and influence both current density and gat- ing properties. The current literature includes reports of numerous FGF12-14 interactions with various Nav alpha subunits. The picture is far from complete, how- Fig. 1. GFP and extracellular biotin acceptor domain tagged Nav1.6 expressed ever, as expression and functional effects vary not only in a cultured hippocampal neuron. Surface channels were detected with streptavidin- conjugated CF640R and are indicated by the red color. Inset shows an enhancement depending on the FGF and Nav isoform partners but of the surface labeling within the dashed line box in the soma. also on the FGF splice variant and cell background (2). Although this diversity has clearly complicated the field, FGFs’ role as Nav channel interacting proteins multiple experimental approaches with cultured hip- has been solidified by the discovery of a highly con- pocampal neurons to support the idea that FGF13 served Nav interaction site within the FGF core domain and FGF14 differentially regulate Nav channel cell sur- that interacts with specific amino acids within the Nav C face expression within somatodendritic and axonal termini (2). FGF14 and Nav channels are enriched at compartments. Thus, FGFs are likely to be central play- the axon initial segment (AIS) of several neuronal types, ers in the regulation of Nav channel cell biology. whereas FGF13 colocalizes with Nav1.6 at nodes of The compartment-specific regulation of FGFs is of Ranvier of dorsal roots of primary afferents (5). Of note great consequence because the polarized distribution is that nodal localization was seen using a pan FGF13 of Nav channel isoforms (Nav1.1−Nav1.9) is critical to antibody, but an antibody that is specific to FGF13S proper neuronal firing. Fig. 1 illustrates the polarized (also known as FGF13A or FHF2A) did not immuno- cell surface distribution of the Nav1.6 isoform in cultured label nodes of Ranvier, showing important isoform hippocampal neurons. Nav1.6 exhibits a strikingly high and splice variant differences (6). Interestingly, muta- plasma membrane density in the AIS compared with tionsinhumanFGF14havebeenlinkedtospinocer- the somatodendritic compartment. Nav localization to ebellar ataxia (7), and mice lacking FGF14 are ataxic the AIS has been extensively studied because this do- (8). Clearly, FGF−Nav channel interactions are worthy main is vital to action potential initiation (10). In contrast, of extensive study, and, in PNAS, Pablo et al. (9) use less is known about Nav channels within the neuronal aDepartment of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 Author contributions: E.J.A. and M.M.T. wrote the paper. The authors declare no conflict of interest. See companion article on page E2665. 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1604831113 PNAS | May 10, 2016 | vol. 113 | no. 19 | 5147–5149 Downloaded by guest on September 27, 2021 cell body, even though these somatic channels are likely involved contrast to the role of FGF13VY in decreasing current density as in the transfer of axonal output information to the rest of the discussed above. Whether these opposing effects are specific to neuron (back-propagation) and to synaptic plasticity (11, 12). each FGF isoform, Nav isoform, or cell type will be important to Studies using chimeric reporter proteins containing the ankyrin- determine. FGF13S and FGF13U both increase current density in binding motif from the Nav1.2 channel implicate selective ND7/23 cells, but it is not clear whether they alter surface expres- endocytosis from the somatic membrane combined with stable sion of the channels in addition to modifying channel properties. tethering to ankyrin within the AIS as a central mechanism in the In fact, modification of biophysical properties has been a recur- establishment of Nav channel polarization (13). Experiments using ring theme in the study of FGF and Nav channel interactions. the full-length Nav 1.6 channel and the single-molecule detection FGF14 has been shown to inhibit neuronal excitability due to a sensitivity of total internal reflection fluorescence microscopy hyperpolarizing shift in the voltage dependence of steady-state demonstrate a direct, ankyrin-dependent vesicular delivery to the AIS where they are immediately immobilized, and ankyrin- Pablo et al. use multiple experimental approaches independent delivery of mobile channels to the soma (14). with cultured hippocampal neurons to support Pablo et al. (9) focused on FGF13 and FGF14 regulation of Nav the idea that FGF13 and FGF14 differentially channel surface expression in cultured DIV 9–12 hippocampal neurons. Immunolabeling of hippocampal neurons showed a con- regulate Nav channel cell surface expression within centration of FGF14 within the AIS in agreement with previous somatodendritic and axonal compartments. work (15). In contrast, FGF13 showed both an axonal and somato- inactivation in both cerebellar granule neurons (17) and dendritic localization pattern. High-resolution images acquired Purkinje neurons (18) without altering Na channel axonal lo- using structured illumination microscopy showed that even the v calization. Together, these data suggest that FGFs can alter AISlocalizationoftheseproteinsdifferedfromeachother, both Na channel localization and biophysical properties in an suggesting different functional roles. The shRNA-mediated knock- v isoform- and cell-type-specific manner. down of these FGFs had differing effects on Nav channel local- ization. FGF14 knockdown decreased the localization of Na The specific mechanisms and extent to which FGFs influ- v ence surface expression are areas for further study, e.g., does channels to the AIS consistent with the work of Laezza et al. FGF13 mediate Na channel capture into clathrin-coated pits? (16) where a mutation in FGF14 that disrupts its interaction v FGF knockdown rescue experiments strongly suggest the ac- with Na channels also showed loss of AIS localization, de- v tion is direct, for FGF13 mutations that prevent Na channel creased current density, and reduced excitability of hippo- v binding fail to rescue or prevent the current increase seen campal neurons. Conversely, shRNA-based knockdown of upon knockdown. Thus far, only indirect evidence suggests FGF13 had no effect on Na proteinexpressionwithinthe v that FGF13 is involved in steady-state clathrin-mediated en- AIS. Whole-cell voltage clamp was used to show that shRNA- docytosis. Direct evidence would include measures of Na based knockdown of FGF13 increased current density, v channel membrane surface stability using single-molecule whereas knockdown of FGF14 decreased current density. imaging techniques of tagged channels (14) and observed Based on these results, Pablo et al. (9) hypothesized that recruitment of Na channels to clathrin-coated pits. Such exper- FGF14 is involved in trafficking Na channels to the AIS, whereas v v iments have been done for other ion channels, such as K 2.1 FGF13 mediates endocytosis of Na channels within the soma- v v (19). Pablo et al. (9) suggest FGF14 may enhance trafficking dendritic domain. The authors next used a biotinylation assay to of Nav channels to the axonal compartment. The authors also measure surface expression of Nav channels in cultured hippo- performed rescue experiments with FGF14 that indicate direct campal neurons after either FGF13 or FGF14 knockdown. FGF14 binding is required for the regulation of Nav expression within the knockdown decreased Nav channel surface expression whereas AIS. Given the highly specific FGF localization within the AIS, FGF13 knockdown increased it. The decreased surface expres- it will be interesting to determine, via either FRET or superre- sion after FGF14 knockdown is consistent with the decreased solution methods, when and where Nav channel isoforms channel expression within the AIS. The authors indirectly assemble with FGF13 and FGF14. It is unclear, in light of addressed the role that FGF13 may play in Nav channel endo- the intracellular AIS trafficking barrier, how some trafficking cytosis by observing the steady-state Nav channel levels after vesicles enter the axon (20). Perhaps FGF14 plays a role in Dynasore treatment. When Dynasore was used to inhibit dyna- getting Nav channel-containing vesicles past this barrier. It min-mediated endocytosis, Nav current levels
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