Fibroblast growth factor 13 stabilizes microtubules to promote Na+ channel function in nociceptive DRG neurons and modulates inflammatory pain

Wang, Qiong; Yang, Jing; Wang, Handong; Shan, Bin; Yin, Chengyu; Yu, Hang; Zhang, Xuerou; Dong, Zishan; Yu, Yulou; Zhao, Ran; Liu, Boyi; Zhang, Hailin; Wang, Chuan

doi:10.1016/j.jare.2020.12.009

Cited by 28 publications

(40 citation statements)

References 34 publications

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“…Notably, PPIs between different iFGFs and different Na v channel isoforms contribute to the generation of phenotypically distinct sodium currents with specialized functions in different tissues [7,9,37,[41][42][43]. For example, the PPI between FGF12 and the Na v 1.5 channel confers important regulatory effects on the I Na of cardiomyocytes [41,42]; the PPI between FGF13 and the Na v 1.7 channel confers important regulatory effects on the I Na of dorsal root ganglion neurons [9,43,44]; and the PPI between FGF14 and the Na v 1.2 and Na v 1.6 channel is important for regulating the I Na and excitability of hippocampal and striatal neurons [7,14,26,37,45]. Despite these diverse and well-established regulatory effects of iFGFs on Na v channels, less is known about cellular signaling molecules that might regulate and enable the targeted modulation conferred by different iFGFs on different Na v channel isoforms.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Dvorak

Tapia

Baumgartner

et al. 2021

Cells

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Voltage-gated Na+ (Nav) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein–protein interactions (PPI) between the Nav channel α subunit and its auxiliary proteins are necessary to reconstitute the full physiological activity of the channel and to fine-tune neuronal excitability. In the brain, the Nav channel isoforms 1.2 (Nav1.2) and 1.6 (Nav1.6) are enriched, and their activities are differentially regulated by the Nav channel auxiliary protein fibroblast growth factor 14 (FGF14). Despite the known regulation of neuronal Nav channel activity by FGF14, less is known about cellular signaling molecules that might modulate these regulatory effects of FGF14. To that end, and building upon our previous investigations suggesting that neuronal Nav channel activity is regulated by a kinase network involving GSK3, AKT, and Wee1, we interrogate in our current investigation how pharmacological inhibition of Wee1 kinase, a serine/threonine and tyrosine kinase that is a crucial component of the G2-M cell cycle checkpoint, affects the Nav1.2 and Nav1.6 channel macromolecular complexes. Our results show that the highly selective inhibitor of Wee1 kinase, called Wee1 inhibitor II, modulates FGF14:Nav1.2 complex assembly, but does not significantly affect FGF14:Nav1.6 complex assembly. These results are functionally recapitulated, as Wee1 inhibitor II entirely alters FGF14-mediated regulation of the Nav1.2 channel, but displays no effects on the Nav1.6 channel. At the molecular level, these effects of Wee1 inhibitor II on FGF14:Nav1.2 complex assembly and FGF14-mediated regulation of Nav1.2-mediated Na+ currents are shown to be dependent upon the presence of Y158 of FGF14, a residue known to be a prominent site for phosphorylation-mediated regulation of the protein. Overall, our data suggest that pharmacological inhibition of Wee1 confers selective modulatory effects on Nav1.2 channel activity, which has important implications for unraveling cellular signaling pathways that fine-tune neuronal excitability.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Dvorak

Tapia

Baumgartner

et al. 2021

Cells

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“…According to the instructions, 800 ng RNA was reversely transcribed using PrimeScriptTM RT reagent Kit with gDNA Eraser (perfect real time) kit (Takara, Japan) ( Wang et al, 2017 ; Wang et al, 2021 ); then, gene-specific mRNA analyses were conducted with SYBR premix ex TaqTMⅡ (TliRnaseH plus) kit (Takara, Japan) as standard protocol. In this study, Gapdh was applied as a reference to normalize the mRNA expression of SCN9A and SCN10A.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain

Wang

Zhang

et al. 2021

Front. Pharmacol.

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Gastrodin (GAS) is the main bioactive ingredient of Gastrodia, a famous Chinese herbal medicine widely used as an analgesic, but the underlying analgesic mechanism is still unclear. In this study, we first observed the effects of GAS on the vincristine-induced peripheral neuropathic pain by alleviating the mechanical and thermal hyperalgesia. Further studies showed that GAS could inhibit the current density of NaV1.7 and NaV1.8 channels and accelerate the inactivation process of NaV1.7 and NaV1.8 channel, thereby inhibiting the hyperexcitability of neurons. Additionally, GAS could significantly reduce the over-expression of NaV1.7 and NaV1.8 on DRG neurons from vincristine-treated rats according to the analysis of Western blot and immunofluorescence results. Moreover, based on the molecular docking and molecular dynamic simulation, the binding free energies of the constructed systems were calculated, and the binding sites of GAS on the sodium channels (NaV1.7 and NaV1.8) were preliminarily determined. This study has shown that modulation of NaV1.7 and NaV1.8 sodium channels by GAS contributing to the alleviation of vincristine-induced peripheral neuropathic pain, thus expanding the understanding of complex action of GAS as a neuromodulator.

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“…In fact, Fgf13 knockout mice show markers of MT instability correlating with a reduction of Na + channel presence at the cell membrane, which is mimicked by colchicine in wild-type mice [229]. In contrast, FGF13 overexpression or PTX application results in more Na + channel proteins being inserted into the surface membrane [229]. The latter finding indicates that exogenous MT modulators can affect neuronal activity, as will be reviewed next.…”

Section: Changes In Excitability and Synaptic Transmission And Their ...mentioning

confidence: 98%

“…These diverse changes in firing could be explained by tau-induced modulation of Na + channel function [223,224] in different neuronal types and compartments [224][225][226][227][228]. Another endogenous MT modulator that influences Na + channel function is FGF13 [229]. In fact, Fgf13 knockout mice show markers of MT instability correlating with a reduction of Na + channel presence at the cell membrane, which is mimicked by colchicine in wild-type mice [229].…”

Section: Changes In Excitability and Synaptic Transmission And Their ...mentioning

confidence: 99%

“…Another endogenous MT modulator that influences Na + channel function is FGF13 [229]. In fact, Fgf13 knockout mice show markers of MT instability correlating with a reduction of Na + channel presence at the cell membrane, which is mimicked by colchicine in wild-type mice [229]. In contrast, FGF13 overexpression or PTX application results in more Na + channel proteins being inserted into the surface membrane [229].…”

Section: Changes In Excitability and Synaptic Transmission And Their ...mentioning

confidence: 99%

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Microtubules as Regulators of Neural Network Shape and Function: Focus on Excitability, Plasticity and Memory

Peña‐Ortega

Robles-Gómez

Xolalpa-Cueva

2022

Cells

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Neuronal microtubules (MTs) are complex cytoskeletal protein arrays that undergo activity-dependent changes in their structure and function as a response to physiological demands throughout the lifespan of neurons. Many factors shape the allostatic dynamics of MTs and tubulin dimers in the cytosolic microenvironment, such as protein–protein interactions and activity-dependent shifts in these interactions that are responsible for their plastic capabilities. Recently, several findings have reinforced the role of MTs in behavioral and cognitive processes in normal and pathological conditions. In this review, we summarize the bidirectional relationships between MTs dynamics, neuronal processes, and brain and behavioral states. The outcomes of manipulating the dynamicity of MTs by genetic or pharmacological approaches on neuronal morphology, intrinsic and synaptic excitability, the state of the network, and behaviors are heterogeneous. We discuss the critical position of MTs as responders and adaptative elements of basic neuronal function whose impact on brain function is not fully understood, and we highlight the dilemma of artificially modulating MT dynamics for therapeutic purposes.

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Fibroblast growth factor 13 stabilizes microtubules to promote Na+ channel function in nociceptive DRG neurons and modulates inflammatory pain

Abstract: Graphical abstract

Cited by 28 publications

References 34 publications

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain

Microtubules as Regulators of Neural Network Shape and Function: Focus on Excitability, Plasticity and Memory

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