Sodium channel modulators

Presented byPresented by
mohan lalmohan lal
M. PharmM. Pharm
mohanlalchoudhary1992@gmail.commohanlalchoudhary1992@gmail.com
Sodium Channels AndSodium Channels And
Their ModulatorsTheir Modulators

Overview
What are Ion channels?
Localization
Molecular Structure of Channel
Gating mechanism
Types of Na+ channel
Sodium Channel Function
Sodium channel modulation
Therapeutic application
2

What are ion channels?
Integral membrane proteins
Responsible for generating
and regulating the electrical
signals through the tissues.
Designed to form water-
filled pores that span the
membrane
Exist in three states resting,
open and closed
3

Localization
Present in many tissues like:
Peripheral nervous system
Brain
Heart
Endocrine cells
Smooth and skeletal muscles
4

 Consist of a large α-subunit associated with other proteins,
such as -subunits.β
 An -subunit forms the core of the channel and is functional onα
its own.
 ß-subunit displays altered voltage dependence and cellular
localization.
 -subunit has four repeat domains, labelled I through IV, eachα
containing six membrane-spanning regions, labelled S1 through
S6.
 The highly conserved S4 region acts as channel's voltage sensor.
 The voltage sensitivity of this channel due to positive amino
acids located at every third position.
 When stimulated by a change in transmembrane voltage, this
region moves toward the extracellular side of the cell
membrane, allowing the channel to become permeable to ions.
Structure of Na+
channel
5

Structure of sodium channelsStructure of sodium channels
6
Representation of the “typical” voltage-activated sodium channel

Structure of α sub-unit
 The ions are conducted through a pore, which can be
broken into two regions.
The more external (i.e., more extracellular) portion of the pore is
formed by the "P-loops" (the region between S5 and S6) of the four
domains. This region is the most narrow part of the pore and is
responsible for its ion selectivity.
The inner portion (i.e., more cytoplasmic) of the pore is formed by
the combined S5 and S6 regions of the four domains.
 The region linking domains III and IV is also important for
channel function. This region plugs the channel after
prolonged activation, inactivating it.
7

Structure of β sub-unit
Two types of β subunits are observed.
β 1- abundantly present in muscles, heart,
and brain. It is bound non covalently.
β 2 forms a single intracellular carboxyl
terminal domain and a large glycosylated
extracellular amino terminal domain. Bound
covalently and forms a heterotrimer.
Main function of these sub units is to
modulate the kinetics of inactivation
8

Gating
Gating, a change between the non-
conducting and conducting state of a
channel
The S4 transmembrane serve as voltage
sensors.
Every third position within these segments
has a positively charged amino acid
(arginine or lysine) residue.
The electrical field, which is negative
inside, exerts a force on these charged
amino acid residues to pull them towards
the intracellular side of the membrane15. 9

Impermeability to other ions
The pore of sodium channels contains a selectivity
filter made of negatively charged amino acid
residues, which attract the positive Na+
ion and
keep out negatively charged ions such as chloride.
The cations flow into a more constricted part of the
pore that is 0.3 by 0.5 nm wide, which is just large
enough to allow a single Na+
ion with a water
molecule associated to pass through.
The larger K+
ion cannot fit through this area.
Differently sized ions also cannot interact as well
with the negatively charged glutamic acid residues
that line the pore.
10

States
Voltage gated sodium channels are present in
three states:
Resting: This is the closed state, which
prevails at the normal resting potential. During
this state, the activation gate is closed and
the inactivation gate is open.
Activated: This is the open state favoured by
brief depolarization. There is an abrupt
flipping open of the activation gate and slow
closure of inactivation gate.
Inactivated: Blocked state resulting from a
trap door-like occlusion of the channel by a
floppy part of the intracellular region of the
channel protein i.e. by the inactivation gate.
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Types Of Na+ Channels
1. Voltage gated – Changes in membrane
polarity open the channel
2. Ligand gated (nicotinic acetylcholine
receptor) – Ligand binding alters
channel/receptor conformation and
opens the pore
3. Mechanically gated (stretch receptor) –
Physical torsion or deformation opens
the channel pore
13

Sodium Channels - Function
Play a central role in the transmission of
action potentials along a nerve
Can be in different functional states
• A resting state when it can respond to a
depolarizing voltage changes
• Activated, when it allows flow of Na+ ions
through it
• Inactivated, when subjected to a
“suprathreshold” potential, the channel will
not open
14

Na+ Channel Modulation
Phosphorylation
serine/threonine and tyrosine kinases & tyrosine
phosphatases.
Mutation
Altered amino acid sequence/structure
Pharmacology
block Na+ channel to reduce the conductance
e.g. Tetrodotoxin, Amioderone, Lidocaine,
Procainamide
Mexilitine ,Ketamine
Proteolysis- (cleavage)
Proteases may cleave specific residues or sequences
that inactivate a channel.

Conditions in which they are usedConditions in which they are used
Epilepsy or convulsions
Neuropathic pain
Neuoprotection in stroke and ischemia
Local anaesthesia
Cardiovascular like arrhythmias
16

Pain
Neuropathic pain arises from increased no.
of sodium channels in sensory nerve fibres.
Hence increased spontaneous action
potential in peripheral nerves
Condition: neuropathic pain, diabetic
neuropathy, trigeminal neuralgia
Drugs used: carbamazepine, lidocaine,
mexilitine etc.
17

Local anesthetics
Sodium channels open when membrane is
depolarized.
Modification of channels may be by
 blockage of the channels
modification of gating behaviour
Local anesthetics block nAch gated channels by
interacting with S6 transmembrane helical domain
LAs enter at the open state and stabilize the
inactivated state of the channels, by shifting the
equilibrium between resting and inactivated state
towards the latter.

Anticonvulsants
 Affects excitability by an action on vol. dependent Na
channels which carry inward current necessary for
generation of action pot.
 Higher the frequency of firing, greater the block
 Antiepileptics bind to depolarized state and reduces
the no. of functional channels for action pot.
generation
19

Thus blockage of sodium channels in brain has a
major neuroprotective effect
Beneficial in ischemia, stroke etc.
Drugs used:
Phenytoin
Carbamazepine
Lamotrigine
Fosphenytoin etc.
20
Continued….

Heart
Depolarization of the resting Na channel to
threshold voltage results in opening of the channel.
This lead to increased permeability of the Na
channel, activated state
Then the channel closes leading to inactivated state
and then again it reverts to resting state which can
be excited for next impulse.
Refractory period depends upon the time taken by
the channel to move from inactivated state to
resting state.
Class I antiarrhythmic drugs increases refractory
Period & decreases rhythm of heart.

Side effects associatedSide effects associated
1. Cardiovascular: reduces systemic B.P. at high
doses, also decreases heart rate, sometimes
cardiac arrest
2. CNS: lidocaine affects myelinated and
unmyelinated axons, paralysis, tremors,
seizures and status epilepticus
3. Diuretics: potassium sparing diuretics block
Na channels with supplement of potassium.
Hence potentiating effect
23

Sodium channel modulators

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Sodium channel modulators