@article{007fa63fbf0542f8af7ecc16053d25c8,
title = "Strong G-Protein-Mediated Inhibition of Sodium Channels",
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.",
keywords = "CaSR, G-protein, G-protein-coupled receptor, GPCR, VGSC, calcium-sensing receptor, excitability, slow inactivation, synaptic transmission neuron, voltage-gated sodium channel",
author = "Mattheisen, {Glynis B.} and Timur Tsintsadze and Smith, {Stephen M.}",
note = "Funding Information: The Casr−/− mice were a kind gift of Dr. Wenhan Chang, University of California, San Francisco (UCSF) and San Francisco Veterans Affairs Medical Center. We are grateful to Dr. Courtney Williams for performing the experiments on synaptic transmission and to Ms. Briana Knight for help with cell culture. We thank the Smith lab members and Drs. Henrique von Gersdorff, Laurence Trussell, and John Williams for productive discussion. This work was supported by grants awarded by the National Institute of General Medical Sciences (NIGMS) (R01 GM097433) and the U.S. Department of Veterans Affairs (BX002547) to S.M.S. In addition, G.B.M. was supported by Achievement Rewards for College Scientists (ARCS), the National Heart, Lung, and Blood Institute (NHLBI) (T32HL083808), and the National Institute of Neurological Disorders and Stroke (NINDS) (F31NS095463). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Funding Information: The Casr −/− mice were a kind gift of Dr. Wenhan Chang, University of California, San Francisco (UCSF) and San Francisco Veterans Affairs Medical Center. We are grateful to Dr. Courtney Williams for performing the experiments on synaptic transmission and to Ms. Briana Knight for help with cell culture. We thank the Smith lab members and Drs. Henrique von Gersdorff, Laurence Trussell, and John Williams for productive discussion. This work was supported by grants awarded by the National Institute of General Medical Sciences (NIGMS) ( R01 GM097433 ) and the U.S. Department of Veterans Affairs ( BX002547 ) to S.M.S. In addition, G.B.M. was supported by Achievement Rewards for College Scientists (ARCS) , the National Heart, Lung, and Blood Institute (NHLBI) ( T32HL083808 ), and the National Institute of Neurological Disorders and Stroke (NINDS) ( F31NS095463 ). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = may,
day = "29",
doi = "10.1016/j.celrep.2018.04.109",
language = "English (US)",
volume = "23",
pages = "2770--2781",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}