An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels

Xu, Mingxuan; Cooper, Edward C.

doi:10.1074/jbc.m115.638932

Cited by 56 publications

(65 citation statements)

References 60 publications

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“…In agreement with this finding, Xu and Cooper reported that the modes of Na V and KCNQ2/3 binding to ank-G differ from each other (10). Thus, our work contributes to a broadening picture of the intricate molecular arrangements that define AIS organization.…”

Section: Discussionsupporting

confidence: 75%

“…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)(12)(13).…”

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confidence: 99%

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FGF14 is a regulator of KCNQ2/3 channels

Pablo

Pitt

2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

FGF14 is a regulator of KCNQ2/3 channels

Pablo

Pitt

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Actin rings are regularly found (at a 190-nm period) along the AIS and distal axon (17,18). Ankyrin G binds subtypes of voltage-gated sodium (Na v ) and potassium (K v ) channels via a specific analogous motif, ensuring their clustering at the AIS (19)(20)(21)(22). In mature neurons of the cortex and hippocampus, Na v 1.2 preferentially localizes to the proximal part of the AIS, while Na v 1.6 and K v 7.2/K v 7.3 cluster along the distal part (12,23,24).…”

mentioning

confidence: 99%

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

Lezmy

Lipinsky

Khrapunsky

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K + channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability. Dual soma-axon patch-clamp recordings combined with axonal Na + imaging and immunocytochemistry revealed that these compensatory alterations were associated with a distal shift of the spike trigger zone and distal relocation of FGF14, Na + , and K v 7 channels but not ankyrin G. The concomitant distal redistribution of FGF14 together with Na v and K v 7 segments along the AIS suggests that these channels relocate as a structural and functional unit. These fast homeostatic changes were independent of L-type Ca 2+ channel activity but were contingent on the crucial AIS protein, protein kinase CK2. Using compartmental simulations, we examined the effects of varying the AIS position relative to the soma and found that AIS distal relocation of both Na v and K v 7 channels elicited a decrease in neuronal excitability. Thus, alterations in M-channel activity rapidly trigger unique AIS plasticity to stabilize network excitability.homeostatic plasticity | axon initial segment | M-current | potassium channel | K v 7

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“…A similar binding motif is found in the distal part of the C-terminus of KCNQ2/ 3 (K V 7.2/K V 7.3). 144 Though Na V channels and K V 7.2/ K V 7.3 channels share an overlapping binding domain on Ankyrin G, the affinity of sodium channels for Ankyrin G is much stronger. The binding of both channel populations to Ankyrin G is modulated by casein kinase 2 (CK2) phosphorylation.…”

Section: Na V Channelsmentioning

confidence: 99%

“…The binding of both channel populations to Ankyrin G is modulated by casein kinase 2 (CK2) phosphorylation. 144 Blocking CK2 activity leads to a dephosphorylation of the binding motif and greater surface dynamics of Na V channels. 18 Alterations to ion channel composition and AIS size are known mechanisms of neuronal excitability tuning.…”

Section: Na V Channelsmentioning

confidence: 99%

Surface dynamics of voltage-gated ion channels

et al. 2016

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Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.

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An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels

Cited by 56 publications

References 60 publications

FGF14 is a regulator of KCNQ2/3 channels

FGF14 is a regulator of KCNQ2/3 channels

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

Surface dynamics of voltage-gated ion channels

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