Transmembrane protein

1. Project Work
TOPIC: VOLTAGE GATED SODIUM ION CHANNEL
USHA
M.SC. BIOINFORMATICS

2. Types of channel
Ligand gated ion channel : These channels open when two or more molecules like
neurotransmitter, secreted from nerve terminal bind to the channel
Voltage gated ion channel : Open in response to step changes in the electric field
Mechanically gated ion channel : Open in response to pressure from outside on the membrane
or some kind of deformations

3. Sodium Channels are
Trans membrane proteins responsible for the voltage-dependent increase in sodium
permeability
Responsible for initiations of actions potentials in neurons and other excitable cells
Target for drugs used in the treatment of epilepsy, cardiac arrhythmias

4. Structure
Composed of α, β subunits
Α subunit consist four homologous domain, each with 6 α helical trans membrane subunits
An α subunit form core of the channel and function on its own
Β subunit displays altered voltage dependence and cellular localizations
Highly conserved S4 subunit act as a voltage sensors domain
Consist inactivation gate
Selectivity filter

5. Structure of α subunit
Mainly consist 6 subunits in each homologous domain
Ion conductions is carried out mainly through pore which is selective in nature
Pore domain is divided into two portions i.e. external part and inner pore
External portions is formed by P-loops that connect S5-S6 subunits
Inner pore is formed by the combined S5-S6 subunits from each domain
All subunits are linked to each other

7. Structure of β subunit
Subunit β1 is non-covalently bounded, has four cysteine in its extracellular domain that
contribute Ig like fold
Subunit β1 abundantly present in muscles, heart, and brain
Subunit β2 is covalently bounded, has five extracellular cysteine and form a disulphide bond to
the α subunit
Subunit β2 forms a single intracellular carboxyl terminal domain and a large glycosylated
extracellular domain
Functioning of β subunits is to modulate the kinetics of activations

8. Selective for sodium ion
Selective filter is made up of negatively charged amino acid residue, which attract only positively
charged sodium ion instead of negative ions like chloride
Pore size is about 0.5 nm, which is enough for passage of a single sodium ion with water
molecule

9. States of sodium ion channel
Resting stage : At this stage, activations gate is closed and inactivation gate is open
Activated stage : Passage of sodium ion takes place in this stage, gate is open in activation stage.
Inactivated stage : Channel remains closed in this stage, no passage of ion

10. Function
Mediate fast depolarization
Conduct electrical impulses throughout nerves, muscles and heart
Target for various type of drug and neurotoxin
Responsible for hormonal secretions

13. Sodium channel blockers
Tetrodotoxin (TTX) and Saxitoxin
Lipid soluble grayanotoxins
Scorpion Toxin
Ketamine
Procainamide
Amioderonn

14. Key features of sodium ion channel
Voltage dependent activations
Rapid inactivation
Selective ion conductance

15. Sodium channel activations
Change in transmembrane potentials results in conformations change in sodium channel
Change in conformations of S4 helices leading to the opening of channel
Rearrangement of S5 and S6 helices
Result in ion conduction

16. References
Hille B: Ion Channels of Excitable Membranes. third ed. Sunderland, MA: Sinauer Associates;
2001.
Catterall WA: From ionic currents to molecular mechanisms: the structure and function of
voltage-gated sodium channels. Neuron 2000, 26:13-25.
Stock L, Delemotte L, Carnevale V, Treptow W, Klein ML: Conduction in a biological sodium
selective channel. J Phys Chem B 2013, 117:3782-3789.
Michael L.klein.;Treptow.W.;Carnevale.V.;Conductions in a biological sodium
channel.J.phys.chem.B 2013,117,3782-3789.
Barber.F.;Raju.S.G.;Carnevale.;Klein.L.;Hinge-bending motions in the pore domain of a bacterial
voltage-gated sodium channel.J.bbamem.2012.
Klein.l.Michael.;Treptow.;Computer Simulations of Voltage-Gated Cation Channel.J.phys.chem
Lett.2013;3;1017-1023.

17. References
Kuyucak;Mahdavi.S.;Mechanism of Ion Permations in Mammalian Voltage-Gated Sodium
Channel.journal.pone.2015.
Delemotte.L.;Tarek.;Omega Currents in Voltage-Gatrd Ion Channel.vol.46.2013,2755-2762.
Gong.Haipeng.;Li.Yang.;Theoretical and simulations studies on Voltage-Gated sodium
Channel.2015.
Klein.L.;Carnevale.;Small molecule modulations of voltage gated sodium channel.2017, 43,156-
162.
Gong.Haipeng.;Li.Yang.;Liu.Huihui.;The mechanism of Sodium-Potassium selectivity in
mammalian Voltage-Gated Sodium Channel Based on Molecular Dynamics
Simulations.2013.;Biophysical.jouranal.104,2401-2409.
Duclohier.Herve.;Structure-Function studies on the voltage-gated sodium
channel.2009.;Biochimica et Biophysica Acta.2374-2379.

18. Thankyou