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Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

ABSTRACT: Tetrodotoxin-sensitive persistent sodium currents, INaP, that activate at subthreshold voltages, have been detected in numerous vertebrate and invertebrate neurons. These currents are believed to be critical for regulating neuronal excitability. However, the molecular mechanism underlying INaP is controversial. In this study, we identified an INaP with a broad range of voltage dependence, from -60mV to 20mV, in a Drosophila sodium channel variant expressed in Xenopus oocytes. Mutational analysis revealed that two variant-specific amino acid changes, I260T in the S4-S5 linker of domain I (ILS4-S5) and A1731V in the voltage sensor S4 of domain IV (IVS4), contribute to the INaP. I260T is critical for the portion of INaP at hyperpolarized potentials. The T260-mediated INaP is likely the result of window currents flowing in the voltage range where the activation and inactivation curves overlap. A1731V is responsible for impaired inactivation and contributes to the portion of INaP at depolarized potentials. Furthermore, A1731V causes enhanced activity of two site-3 toxins which induce persistent currents by inhibiting the outward movement of IVS4, suggesting that A1731V inhibits the outward movement of IVS4. These results provided molecular evidence for the involvement of distinct mechanisms in the generation of INaP: T260 contributes to INaP via enhancement of the window current, whereas V1731 impairs fast inactivation probably by inhibiting the outward movement of IVS4.

SUBMITTER: Gao R

PROVIDER: S-EPMC4482340 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

Gao R R Du Y Y Wang L L Nomura Y Y Satar G G Gordon D D Gurevitz M M Goldin A L AL Dong K K

Neuroscience 20140321

Tetrodotoxin-sensitive persistent sodium currents, INaP, that activate at subthreshold voltages, have been detected in numerous vertebrate and invertebrate neurons. These currents are believed to be critical for regulating neuronal excitability. However, the molecular mechanism underlying INaP is controversial. In this study, we identified an INaP with a broad range of voltage dependence, from -60mV to 20mV, in a Drosophila sodium channel variant expressed in Xenopus oocytes. Mutational analysis ...[more]

PMID: 24662849

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Project description:Pulsed focused ultrasound (pFUS) technology is being developed for clinical neuro/immune modulation and regenerative medicine. Biological signal transduction of pFUS forces can require mechanosensitive or voltage-gated plasma membrane ion channels. Previous studies suggested pFUS is capable of activating either channel type, but their mechanistic relationship remains ambiguous. We demonstrated pFUS bioeffects increased mesenchymal stem cell tropism (MSC) by altering molecular microenvironments through cyclooxygenase-2 (COX2)-dependent pathways. This study explored specific relationships between mechanosensitive and voltage-gated Ca2+ channels (VGCC) to initiate pFUS bioeffects that increase stem cell tropism. Methods: Murine kidneys and hamstring were given pFUS (1.15 or 1.125 MHz; 4MPa peak rarefactional pressure) under ultrasound or magnetic resonance imaging guidance. Cavitation and tissue displacement were measure by hydrophone and ultrasound radiofrequency data, respectively. Elastic modeling was performed from displacement measurements. COX2 expression and MSC tropism were evaluated in the presence of pharmacological ion channel inhibitors or in transient-receptor-potential-channel-1 (TRPC1)-deficient mice. Immunohistochemistry and co-immunoprecipitation examined physical channel relationships. Fluorescent ionophore imaging of cultured C2C12 muscle cells or TCMK1 kidney cells probed physiological interactions. Results: pFUS induced tissue deformations resulting in kPa-scale forces suggesting mechanical activation of pFUS-induced bioeffects. Inhibiting VGCC or TRPC1 in vivo blocked pFUS-induced COX2 upregulation and MSC tropism to kidneys and muscle. A TRPC1/VGCC complex was observed in plasma membranes. VGCC or TRPC1 suppression blocked pFUS-induced Ca2+ transients in TCMK1 and C2C12 cells. Additionally, Ca2+ transients were blocked by reducing transmembrane Na+ potentials and observed Na+ transients were diminished by genetic TRPC1 suppression. Conclusion: This study suggests that pFUS acoustic radiation forces mechanically activate a Na+-containing TRPC1 current upstream of VGCC rather than directly opening VGCC. The electrogenic function of TRPC1 provides potential mechanistic insight into other pFUS techniques for physiological modulation and optimization strategies for clinical implementation.

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Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

Publications

Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.

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