FGF14 is a regulator of KCNQ2/3 channels

Abstract

KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization. FGF14 knockdown leads to a reduction of KCNQ2 in the AIS and a reduction in whole-cell KCNQ currents. FGF14 positively regulates KCNQ2/3 channels in a simplified expression system. FGF14 interacts with KCNQ2 at a site distinct from the FGF14-VGSC interaction surface, thus enabling the bridging of Na V 1.6 and KCNQ2. These data implicate FGF14 as an organizer of channel localization in the AIS and provide insight into the coordination of KCNQ and VGSC conductances in the regulation of membrane potential.FGF14 | KCNQ2 | fibroblast growth factor homologous factors | axon initial segment | ankyrin-G N eurons express a wide diversity of ion channels and yet are able to target different channels specifically to cellular subcompartments such as the axon initial segment (AIS) (1, 2). Among the channels specifically targeted to the AIS are the voltage-gated sodium channels (VGSCs) and KCNQ2/3 (Kv7.2/ Kv7.3) voltage-gated potassium channels (3-5). VGSCs are trapped in the AIS through binding to the scaffolding protein ankyrin-G (ank-G), which anchors transmembrane molecules to the spectrin-actin cytoskeleton (4, 6, 7). Localization of KCNQ2/3 channels of the K V 7 family to the AIS has been proposed to follow the model of VGSCs, because KCNQ2/3 channels contain the same ank-G binding motifs that trap VGSCs (8). Moreover, VGSCs and KCNQ2/3 channels both bind to the ankyrin repeats in ank-G, albeit at distinct but overlapping interaction sites (9, 10). However, other determinants for AIS localization outside of the ankyrin-binding motif have been described, thus pointing to additional modes of regulation (11-13).The tight colocalization of K V 7 channels with VGSCs has been postulated to confer specific coregulatory properties. In the soma, dendrites, and AIS, K V 7 channels attenuate subthreshold depolarization by opposing a VGSC persistent current, whereas in the nodes, K V 7 channels stabilize the membrane potential and protect VGSC channels from inactivation (14). Although ank-G serves as an AIS anchor for both K V 7 channels and VGSCs, simultaneous binding of both channels to one ank-G molecule has not been demonstrated, and the molecular mechanisms underlying the coordination between Kv7 channels and VGSCs are incompletely understood. We hypothesized that fibroblast growth factor homologous factors (FHFs), a subfamily (FGF11-14) of fibroblast growth factors that function as intracellular modulators of VGSCs (15,16) channels is not known. Here, we focused on the neuronally restricted FGF14 because...

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

“…For example, in the avian nucleus magnocellularis neurons, K v 7.2 immunoreactivity was distributed along the entire AIS (50). In agreement with our findings and in line with previous work (38,39), FGF14, which physically bridges the K v 7 and Na v channels and entirely localizes to the proximal AIS (38,39), exhibited a shorter length than that of ankyrin G (∼24 μm versus 33 μm) in our preparation (Fig. 2C and Fig.…”

“…This FGF14 distal relocation is like that of the K v 7.3 and Na v channels. In line with previous work (38,39), the length of the FGF14 label was shorter than that of ankyrin G (∼24 μm versus 33 μm) ( Fig. 2C and Fig.…”

“…FGF14 was proposed to be an organizer of Na v 1.6 and K v 7 channel localization in the AIS, suggesting their coordinated function (38). If this is indeed the case, one should expect that FGF14 would follow similar homeostatic changes after extended M-channel inhibition.…”

Divide, multitask, and conquer: Coordination in channel regulation

“…2 Knockdown of FGF13, on the other hand, had no effect on KCNQ2 localization. While VGSCs initiate the action potential, neuronal KCNQ channels control resting membrane potential and are important in relieving the voltagedependent inactivation of VGSCs.…”

“…In the past year, we described 2 modes of ion channel regulation mediated by fibroblast growth factor homologous factors (FHFs) in neurons. 1,2 FHFs (FGF11-FGF14) are members of the fibroblast growth factor (FGF) family but function differently than canonical FGFs. 3 FHFs, in contrast to canonical FGFs, interact with voltage-gated sodium channels (VGSCs) and modify VGSC behavior.…”