SUMMARY 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 GDPbs, 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.

Endogenous cannabinoid signaling is vital for important brain functions and can be modified pharmacologically to treat pain, epilepsy, and posttraumatic stress disorder. Endocannabinoid mediated changes to excitability are predominantly attributed to 2-arachidonoylglycerol at synapses. Here we identify a pathway in the neocortex by which anandamide, the other major endocannabinoid, powerfully inhibits sodium conductances in the soma resulting in a loss of neuronal excitability. This pathway is mediated by the cannabinoid receptor, and its activation results in a decrease of recurrent action potential generation. The synthetic cannabinoid, Win-55, also inhibits VGSC currents indicating this pathway is positioned to mediate the actions of exogenous cannabinoids.

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