Strong G-Protein-Mediated Inhibition of Sodium Channels

Abstract

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.

Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels

“…Could CaSR stimulation activate G-proteins and regulate the V 0.5 for VGSC currents ( Figure 3E,F )? In neocortical neurons, G-protein activation hyperpolarized VGSC gating and this was blocked by GDPβS ( Mattheisen et al, 2018 ) which is inconsistent with the effect we observed here. Other possible explanations are that CaSR could regulate VGSC subunit expression or post translational modification ( Cantrell et al, 1996 ; Zhang et al, 2019 ), and this may represent a compensatory mechanism similar to that observed with other mutant mouse models ( Jun et al, 1999 ).…”

CaSR modulates sodium channel-mediated Ca2+-dependent excitability

“…Could CaSR stimulation activate G-proteins and regulate the basal V 0.5 for VGSC currents (Figure 3E,F)? In neocortical neurons, G-protein activation hyperpolarized VGSC gating and this was blocked by GDPβS (Mattheisen et al, 2018) which is inconsistent with the effect we observed here. Other possible explanations are that CaSR regulates VGSC subunit expression or post translational modification (Cantrell et al, 1996; Zhang et al, 2019).…”

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

“…G-protein modulation of voltage-gated sodium channels is another well-characterized general phenomenon within the nervous system, mediated in part by PKA phosphorylation of sites between homology domains I and II, affecting both peak transient and persistent components of sodium conductance (154,155). A possible role for opioid modulation of voltage-gated sodium channels in OIRD has yet to be investigated.…”