Strong G-Protein-Mediated Inhibition of Sodium Channels

Glynis B. Mattheisen, Timur Tsintsadze, Stephen Smith

Research output: Contribution to journalArticle

Abstract

Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function may be strongly inhibited by local anesthetic and antiepileptic drugs and modestly modulated via second messenger pathways. Here, we report that the allosteric modulators of the calcium-sensing receptor (CaSR) cinacalcet, calindol, calhex, and NPS 2143 completely inhibit VGSC current in the vast majority of cultured mouse neocortical neurons. This form of VGSC current block persisted in CaSR-deficient neurons, indicating a CaSR-independent mechanism. Cinacalcet-mediated blockade of VGSCs was prevented by the guanosine diphosphate (GDP) analog GDPβs, indicating that G-proteins mediated this effect. Cinacalcet inhibited VGSCs by increasing channel inactivation, and block was reversed by prolonged hyperpolarization. Strong cinacalcet inhibition of VGSC currents was also present in acutely isolated mouse cortical neurons. These data identify a dynamic signaling pathway by which G-proteins regulate VGSC current to indirectly modulate central neuronal excitability. Mattheisen et al. demonstrate a G-protein-dependent pathway that strongly inhibits voltage-gated sodium channel currents in the vast majority of cortical neurons. The mechanism involves profound slowing of recovery from inactivation. The strong and widespread effects on voltage-gated sodium channels position this signaling pathway to have substantial influence on neuronal excitability.

Original languageEnglish (US)
Pages (from-to)2770-2781
Number of pages12
JournalCell Reports
Volume23
Issue number9
DOIs
StatePublished - May 29 2018

Keywords

  • calcium-sensing receptor
  • CaSR
  • excitability
  • G-protein
  • G-protein-coupled receptor
  • GPCR
  • slow inactivation
  • synaptic transmission neuron
  • VGSC
  • voltage-gated sodium channel

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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