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Updated: Feb 9, 2026

Examining Monosynaptic Connections in Drosophila Using Tetrodotoxin Resistant Sodium Channels
Published on: February 14, 2018
Strong G-Protein-Mediated Inhibition of Sodium Channels
Glynis B Mattheisen1, Timur Tsintsadze1, Stephen M Smith1
1Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, OR 97239, USA; Section of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, OR 97239, USA.
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.
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