Presented by Presented by mohan lal mohan lal

M. PharmM. Pharm mohanlalchoudhary1992@gmail.commohanlalchoudhary1992@gmail.com

Sodium Channels And Sodium Channels And Their ModulatorsTheir Modulators

OverviewWhat are Ion channels?LocalizationMolecular Structure of Channel Gating mechanismTypes of Na+ channelSodium Channel FunctionSodium channel modulationTherapeutic 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 systemBrainHeartEndocrine cellsSmooth 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 on αits own.

ß-subunit displays altered voltage dependence and cellular localization.

-subunit has four repeat domains, labelled I through IV, each αcontaining 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

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

Structure of α sub-unitThe 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-unitTwo 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

GatingGating, 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.

11

12

Types Of Na+ Channels1. Voltage gated – Changes in membrane

polarity open the channel2. 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 ModulationPhosphorylation serine/threonine and tyrosine kinases & tyrosine

phosphatases.Mutation Altered amino acid sequence/structurePharmacology 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 convulsionsNeuropathic painNeuoprotection in stroke and ischemiaLocal anaesthesiaCardiovascular like arrhythmias

16

PainNeuropathic pain arises from increased no.

of sodium channels in sensory nerve fibres.Hence increased spontaneous action

potential in peripheral nervesCondition: neuropathic pain, diabetic

neuropathy, trigeminal neuralgiaDrugs used: carbamazepine, lidocaine,

mexilitine etc.

17

Local anesthetics

Sodium channels open when membrane is depolarized.

Modification of channels may be by blockage of the channelsmodification 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:

PhenytoinCarbamazepineLamotrigineFosphenytoin 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.

22

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

Thank you…..

24