Effects of Deltamethrin Acute Exposure on Nav1.6 Channels and Medium Spiny Neurons of the Nucleus Accumbens

Tapia, Cynthia M.; Folorunso, Oluwarotimi; Singh, A.K.; McDonough, Kathleen E; Laezza, Fernanda

doi:10.1016/j.tox.2020.152488

Cited by 12 publications

(11 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To study long-term inactivation (LTI), a four-sweep protocol consisting of four 20 ms duration, 0 mV depolarizing pulses separated by 40 ms duration −90 mV interpulse recovery phases from a -90 mV holding potential was employed ( Dover et al, 2010 ; Barbosa et al, 2017 ; Liu et al, 2019 ; Tapia et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14

Singh

Dvorak

Tapia

et al. 2021

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

The voltage-gated Na+ (Nav) channel is a primary molecular determinant of the initiation and propagation of the action potential. Despite the central role of the pore-forming α subunit in conferring this functionality, protein:protein interactions (PPI) between the α subunit and auxiliary proteins are necessary for the full physiological activity of Nav channels. In the central nervous system (CNS), one such PPI occurs between the C-terminal domain of the Nav1.6 channel and fibroblast growth factor 14 (FGF14). Given the primacy of this PPI in regulating the excitability of neurons in clinically relevant brain regions, peptides targeting the FGF14:Nav1.6 PPI interface could be of pre-clinical value. In this work, we pharmacologically evaluated peptides derived from FGF14 that correspond to residues that are at FGF14’s PPI interface with the CTD of Nav1.6. These peptides, Pro-Leu-Glu-Val (PLEV) and Glu-Tyr-Tyr-Val (EYYV), which correspond to residues of the β12 sheet and β8-β9 loop of FGF14, respectively, were shown to inhibit FGF14:Nav1.6 complex assembly. In functional studies using whole-cell patch-clamp electrophysiology, PLEV and EYYV were shown to confer differential modulation of Nav1.6-mediated currents through mechanisms dependent upon the presence of FGF14. Crucially, these FGF14-dependent effects of PLEV and EYYV on Nav1.6-mediated currents were further shown to be dependent on the N-terminal domain of FGF14. Overall, these data suggest that the PLEV and EYYV peptides represent scaffolds to interrogate the Nav1.6 channel macromolecular complex in an effort to develop targeted pharmacological modulators.

show abstract

Section: Methodsmentioning

confidence: 99%

Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14

Singh

Dvorak

Tapia

et al. 2021

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Clampex 9.2 software (Molecular Devices) was used to set experimental parameters, and electrophysiological equipment was interfaced to this software using a Digidata 1200 analog-digital interface (Molecular Devices). Acquired data was then analyzed as previously described [27,28,30,31,33].…”

Section: Whole-cell Voltage-clamp Recordings In Heterologous Cellsmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Pyrethroid insecticides exert their neurotoxic action by delaying the inactivation of voltage-gated sodium channels (VGSC or Na v ). Deltamethrin, a type II pyrethroid, has been shown to alter the function of multiple Na v isoforms in in vitro studies, voltage-clamp experiments and in studies addressing the mode of action in mosquito and other arthropods (Tapia et al, 2020). (2): An inverse association was also observed for cis-DCCA at 1 year, which may partially account for the inverse association observed for 3-PBA.…”

Section: Interpretation Of Results and Potential Mechanism Underlying The Associations Foundmentioning

confidence: 99%

“…Deltamethrin also altered the expression of MSN proteins important for NAc signalling, indicating that these cells are especially sensitive to pyrethroid exposure (Magby and Richardson, 2017; Richardson et al., 2015). These observations point out to a possible mechanism for deltamethrin toxicity involving disruption of the NAc circuitry over time, increasing the risk of ADHD and other NDDs (Tapia et al., 2020).…”

Section: Assessmentmentioning

confidence: 99%

Development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment

Hernandez-Jerez¹,

Adriaanse²,

Aldrich³

et al. 2021

EFS2

View full text Add to dashboard Cite

The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self-task mandate (EFSA-Q-2019-00100), two adverse outcome pathway (AOP)-informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence-based-approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high-throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidencebased AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT-IVB for hazard identification and characterisation and illustrate the usefulness of an AOP-informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP-informed IATA methodology and of the DNT-IVB in the regulatory risk assessment of pesticides.

show abstract

Effects of Deltamethrin Acute Exposure on Nav1.6 Channels and Medium Spiny Neurons of the Nucleus Accumbens

Cited by 12 publications

References 54 publications

Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14

Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14

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

Development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment

Contact Info

Product

Resources

About