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Voltage-gated sodium channels. Xiao Yu Institute of Physiology Shandong University, School of Medicine 2012-11-10. Sodium channel genes are latecomers to the 6TM Family. (Zakon HH, PNAS 2012). Sodium Channels - Structure.

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voltage gated sodium channels

Voltage-gated sodium channels

Xiao Yu

Institute of Physiology

Shandong University, School of Medicine


sodium channels structure
Sodium Channels - Structure
  • Composed of α, β-1 and β-2 subunits, but the large α-subunits carries most of the functional properties
  • 4 repeated motifs, each with 6 transmembrane domains
  • All linked together
  • Contain a voltage “sensor”/ligand binding domain (method of activation)
  • The hydrophobic S4 segment (voltage “sensor”) is found in all voltage gated Na+ channels and is absent in ligand gated Na+ channels
  • Selectivity filter (shell of hydration)
  • Inactivation gate
  • 1. Physiological studies
  • 2. Pharmacological studies
  • 3. Biochemical studies
  • 4. Pathological and further studies
physiological properties of vgscs activation inactivation recovery
Physiological properties of VGSCs: activation, inactivation, recovery

(Neuroscience: Exploring the Brain 2007)

voltage gated sodium channel activation
Voltage-gated sodium channel: activation

(Lou, et al, J Physiol 2003)

hyperpolarization is necessary for depolarization induced sodium currents in pancreatic beta cells
Hyperpolarization is necessary for depolarization-induced sodium currents in pancreatic beta cells
summary i
Summary I
  • 1. VGSC currents are voltage-gated inward currents.
  • 2. VGSCs perform fast activation and fast inactivation.
  • 3. Inactivation and recovery of VGSCs are diverse.

Tetrodotoxin - Pufferfish

Saxitoxin - Paralytic Shellfish Poisoning

Soong, T.W. and B.Venkatesh.Trends Genetics, 22; 621-626 (2006)


TTX and STX- Molecular Mimics

Soong, T.W. and B.Venkatesh.Trends Genetics, 22; 621-626 (2006)


Y/N substitution in Pufferfish = TTX resistant

VGSC and binding site for TTX

Soong, T.W., and B. Venkatesh, Trends Genetics, 22; 621-626 (2006)


Blocking of WT and mutant VGSCs by TTX and STX

E/D mutation – TTX/STX-resistance

blocking by TTX (a) and STX (b)Scale bars, 1 nA and 1 ms.

Bricelj, V.M. et al., Nature, 434; 763-767 (2005)


O-conotoxin (MrVIB) selectively blocks Nav1.8 ---- TTX-resistant current in DRG

TTX-resistant sodium channel (Nav1.8)

No effect onthe persistent TTX-R Na current Nav1.9)

Ekberg,J et al, PNAS(2006)

summary ii
Summary II药理学--电压门控钠通道分类
  • 神经类钠通道(对TTX敏感性高、对μCTX敏感性低)
  • 骨骼肌类钠通道(对TTX和μCTX敏感性均高)
  • 心肌类钠通道(对TTX和μCTX敏感性均低)。
sodium channels co immunoprecipitate with rptp b
Sodium channels co-immunoprecipitate with RPTPb

Increase postnatally


Constant levels

Ratcliffe CF, et al.

Nature Neuroscience 2000

summary iii
Summary III
  • 1. VGSC are regulated with phosphatase and kinase
  • 2. Biochemical studies and physiological studies on VGSCs are put together.
pain and nav1 7
Pain and Nav1.7


insensitivity to pain


Paroxysmal extreme

pain disorder




Primary erythromelalgia


more snps
More SNPs





What can go wrong?







  • Expression models
  • cRNA or cDNA injection into Xenopus oocytes
  • Transfection of mammalian cell culture
  • Methods
  • Electrophysiology
  • Pharmacology
  • Immunocytochemistry
  • Fluorescence imaging of tagged proteins
take home messages
Take home messages
  • 1. Na channels physiological properties are diverse and crucial.
  • 2. Na channels are regulated by drugs, enzymes and single mutation of themselves.