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 language | English (US) |
|---|---|
| Pages (from-to) | 2770-2781 |
| Number of pages | 12 |
| Journal | Cell Reports |
| Volume | 23 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 29 2018 |
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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)
Cite this
Strong G-Protein-Mediated Inhibition of Sodium Channels. / Mattheisen, Glynis B.; Tsintsadze, Timur; Smith, Stephen.
In: Cell Reports, Vol. 23, No. 9, 29.05.2018, p. 2770-2781.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Strong G-Protein-Mediated Inhibition of Sodium Channels
AU - Mattheisen, Glynis B.
AU - Tsintsadze, Timur
AU - Smith, Stephen
PY - 2018/5/29
Y1 - 2018/5/29
N2 - 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.
AB - 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.
KW - calcium-sensing receptor
KW - CaSR
KW - excitability
KW - G-protein
KW - G-protein-coupled receptor
KW - GPCR
KW - slow inactivation
KW - synaptic transmission neuron
KW - VGSC
KW - voltage-gated sodium channel
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U2 - 10.1016/j.celrep.2018.04.109
DO - 10.1016/j.celrep.2018.04.109
M3 - Article
VL - 23
SP - 2770
EP - 2781
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 9
ER -