1. By – SARVESH MAURYA
DR.L.H.HIRANANDANI
COLLEGE OF PHARMACY.

2.  MOLECULAR ARCHITECTURE OF ION
CHANNELS
• Ion channels are large and elaborate molecules. All
consist of several (often four) domains, which are
similar or identical to each other, organised either as an
oligomeric array of separate subunits, or as one large
protein.
• Each subunit or domain contains a bundle of two to six
membrane-spanning helices. Most ligand-gated
channels have the basic structure, comprising a
pentameric array of non-identical subunits, each
consisting of four transmembrane helices.
•The large extracellular N-terminal region contains the
ligand-binding region

3. Types Of Na+ Channels
•Voltage gated –
Changes in membrane
polarity open the
channel

4. •Ligand gated (nicotinic
acetylcholine receptor) – Ligand
binding alters channel/receptor
conformation and opens the
pore
•Mechanically gated (stretch receptor) –
Physical torsion or deformation opens the
channel pore

5. Voltage-gated sodium channels:
Introduction
• Voltage-gated sodium channels are responsible for action potential initiation and
propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types.
• They are also expressed at low levels in nonexcitable cells, where their physiological role is
unclear. Sodium channels are the founding members of the ion channel superfamily in terms
of their discovery as a protein and determination of their amino acid sequence.
Sodium Channel Subunits
• Sodium channels consist of a highly processed α subunit, which is approximately 260 kDa,
associated with auxiliary β subunits Sodium channels in the adult central nervous system and
heart contain β1 through β4 subunits, whereas sodium channels in adult skeletal muscle have
only the β1 subunit .
• The pore-forming α subunit is sufficient for functional expression, but the kinetics and
voltage dependence of channel gating are modified by the β subunits, and these auxiliary
subunits are involved in channel localization and interaction with cell adhesion molecules,
extracellular matrix, and intracellular cytoskeleton.

6. •The α subunits are organized in four homologous domains (I-IV), each of which contain six
transmembrane α helices (S1-S6) and an additional pore loop located between the S5 and
S6 segments (Fig. 1). The pore loops line the outer, narrow entry to the pore, whereas the
S5 and S6 segments line the inner, wider exit from the pore. The S4 segments in each
domain contain positively charged amino acid residues at every third position.
•These residues serve as gating charges and move across the membrane to initiate channel
activation in response to depolarization of the membrane. The short intracellular loop
connecting homologous domains III and IV serves as the inactivation gate, folding into the
channel structure and blocking the pore from the inside during sustained depolarization of
the membrane.
FIG. 1. Transmembrane organization of sodium channel subunits.

7. •The primary structures of the subunits of the voltage-gated ion channels are illustrated as
transmembrane-folding diagrams. Cylinders represent probable α-helical segments. Bold lines
represent the polypeptide chains of each subunit, with length approximately proportional to the
number of amino acid residues in the brain sodium channel subtypes.
•The extracellular domains of the β1 and β2 subunits are shown as immunoglobulin-like folds.
ψ, sites of probable N-linked glycosylation; P, sites of demonstrated protein phosphorylation by
protein kinase A (circles) and protein kinase C (diamonds); shaded, pore-lining S5-P-S6
segments; white circles, the outer (EEDD) and inner (DEKA) rings of amino residues that form
the ion selectivity filter and tetrodotoxin binding site; ++, S4 voltage sensors; h in shaded
circle, inactivation particle in the inactivation gate loop; open shaded circles, sites implicated in
forming the inactivation gate receptor.
•Sites of binding of α- and β-scorpion toxins and a site of interaction between α and β1
subunits are also shown.

8. Sodium Channel Classification and Nomenclature
 In this nomenclature system, the name of an individual channel consists of the chemical
symbol of the principal permeating ion (Na) with the principal physiological regulator (voltage)
indicated as a subscript (NaV).
 The number following the subscript indicates the gene subfamily (currently only NaV1), and
the number following the full point identifies the specific channel isoform (e.g., NaV1.1). This
last number has been assigned according to the approximate order in which each gene was
identified. Splice variants of each family member are identified by lowercase letters following
the numbers (e.g., NaV1.1a).

9. Genetic mutations in sodium channel genes give rise to channelopathies and
clinical disease
Channel
nomenclature
Gene
Chromosomal
location
(human)
Tetrodotoxin
sensitivity
Major tissue
expression
Effect of
mutation
Nav1.1 SCN1A 2q24 CNS, PNS Epilepsy
Nav1.2 SCN2A 2q23–24 CNS, PNS Epilepsy
Nav1.3 SCN3A 2q24 CNS, PNS None reported
Nav1.4 SCN4A 17q23–25 Skeletal muscle
Myotonia,
periodic
paralysis
Nav1.5 SCN5A 3p21 Heart
Long QT,
Brugada
syndrome,
progressive
familial heart
block
Nav1.6 SCN8A 12q13 CNS, PNS
Cerebellar
atrophy
Nav1.7 SCN9A 2q24
PNS (SNS and
PAs)
Increased and
decreased pain
sensitivity
Voltage-gated sodium channel nomenclature, chromosomal location and tissue distribution

10. Sodium Channels - Function
Can be in different functional states (3)
A resting
state
• when it can respond to a depolarizing voltage
changes
Activated
• when it allows flow of Na+ ions through the
Inactivated
• when subjected to a “suprathreshold”
potential, the channel will not open

11. Na + Channel Blockers/Pharmacological Agents
• Tetrodotoxin (TTX)(blocks voltage gated sodium
channel)
• Amioderone (blocks cardiac channel)
• Lidocaine (blocks voltage sodium channel in neuronal
cell membrane)
• Procainamide
• Mexilitine
• Ketamine

12. Tetrodoxin
•Tetrodotoxin is the poison that is produced by the puffer fish and a number of other animals. It
is a virulent poison, the LD50 for the mouse is 10 nanograms.
• It acts by blocking the conduction of nerve impulses along nerve fibers and axons. The victim
eventually dies from respiratory paralysis.
Saxitoxin, a natural product
from dinoflagellates, acts in a similar way and
is also a potent nerve poison."

13. If tetrodotoxin is such a powerful toxin why does
it not poison the host?
This is a common question in virtually all cases where a toxin is
present.
The sodium ion channel in the host must be different than that
of the victim.
It must not be susceptible to the toxin.

14. It has been demonstrated for one of the pufferfish that the protein of
the sodium ion channel has undergone a mutation that changes the
amino acid sequence making the channel insensitive to tetrodotoxin.
The spontaneous mutation that caused this structural change is
beneficial to the pufferfish because it allowed it to incorporate the
symbiotic bacteria and utilize the toxin it produces to its best advantage,
A single point mutation in the amino acid sequence of the sodium-ion
channel in this species renders it immune from being bound and
blockaded by TTX.

15. Side effects occur while taking Amiodarone
Dizziness
Cough
trembling or shaking of the hands
lightheadedness, or
fainting, Dizziness
Common
side
efects
unusual and
uncontrolled
movements of
the body
shortnes
s of
breath
Cough,
fever
(slight)
numbness or
tingling in the
fingers or toes

16. Blue-gray coloring of
the skin on the face,
neck, and arms
Less common
side effects
blurred vision or blue-green
halos seen around
objects
fast or irregular
heartbeat
dry, puffy skin
dry eyes

17. •REFERENCES
•William A. Catterall, Alan L. Goldin, Stephen G. Waxman.
Voltage-gated sodium channels, introductory chapter.
•Adapted from the original article
in Pharmacological Reviews