PMID- 29847805
OWN - NLM
STAT- MEDLINE
DCOM- 20191105
LR  - 20210109
IS  - 2211-1247 (Electronic)
VI  - 23
IP  - 9
DP  - 2018 May 29
TI  - Strong G-Protein-Mediated Inhibition of Sodium Channels.
PG  - 2770-2781
LID - S2211-1247(18)30709-5 [pii]
LID - 10.1016/j.celrep.2018.04.109 [doi]
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 GDPbetas, 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.
CI  - Published by Elsevier Inc.
FAU - Mattheisen, Glynis B
AU  - Mattheisen GB
AD  - Department 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.
FAU - Tsintsadze, Timur
AU  - Tsintsadze T
AD  - Department 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.
FAU - Smith, Stephen M
AU  - Smith SM
AD  - Department 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. 
      Electronic address: smisteph@ohsu.edu.
LA  - eng
GR  - F31 NS095463/NS/NINDS NIH HHS/United States
GR  - I01 BX002547/BX/BLRD VA/United States
GR  - R01 GM097433/GM/NIGMS NIH HHS/United States
GR  - T32 HL083808/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0 (Receptors, Calcium-Sensing)
RN  - 0 (Voltage-Gated Sodium Channel Blockers)
RN  - 0 (Voltage-Gated Sodium Channels)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - UAZ6V7728S (Cinacalcet)
SB  - IM
MH  - Allosteric Regulation/drug effects
MH  - Animals
MH  - Animals, Newborn
MH  - Cinacalcet/pharmacology
MH  - GTP-Binding Proteins/*metabolism
MH  - Guanosine Triphosphate/metabolism
MH  - Ion Channel Gating/drug effects
MH  - Mice
MH  - Neocortex/cytology
MH  - Neurons/cytology/drug effects/metabolism
MH  - Receptors, Calcium-Sensing/agonists/metabolism
MH  - Voltage-Gated Sodium Channel Blockers/pharmacology
MH  - Voltage-Gated Sodium Channels/*metabolism
PMC - PMC6203318
MID - NIHMS1508930
OTO - NOTNLM
OT  - CaSR
OT  - G-protein
OT  - G-protein-coupled receptor
OT  - GPCR
OT  - VGSC
OT  - calcium-sensing receptor
OT  - excitability
OT  - slow inactivation
OT  - synaptic transmission neuron
OT  - voltage-gated sodium channel
COIS- DECLARATION OF INTERESTS The authors declare no competing interests.
EDAT- 2018/05/31 06:00
MHDA- 2019/11/07 06:00
PMCR- 2018/10/26
CRDT- 2018/05/31 06:00
PHST- 2017/10/12 00:00 [received]
PHST- 2018/03/26 00:00 [revised]
PHST- 2018/04/25 00:00 [accepted]
PHST- 2018/05/31 06:00 [entrez]
PHST- 2018/05/31 06:00 [pubmed]
PHST- 2019/11/07 06:00 [medline]
PHST- 2018/10/26 00:00 [pmc-release]
AID - S2211-1247(18)30709-5 [pii]
AID - 10.1016/j.celrep.2018.04.109 [doi]
PST - ppublish
SO  - Cell Rep. 2018 May 29;23(9):2770-2781. doi: 10.1016/j.celrep.2018.04.109.