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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

2012-11-10

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
outline
Outline
  • 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.
slide14

Tetrodotoxin - Pufferfish

Saxitoxin - Paralytic Shellfish Poisoning

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

slide15

TTX and STX- Molecular Mimics

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

slide16

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)

slide17

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)

slide18

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

embryogenesis

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

congenital

insensitivity to pain

先天性痛不敏感症

Paroxysmal extreme

pain disorder

突发性疼痛异常

erythromelalgia

(原发性)肢端红痛症

Primary erythromelalgia

PE

more snps
More SNPs

钾离子恶化性肌强直病,PAM

高血钾性周期性麻痹,HyperPP

先天性肌强直病,PMC

slide33

What can go wrong?

permeation

kinetics

Na+

targeting

translation

assembly

  • 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.