VPB 121: Veterinary Physiology - II (2+1)

THE VOLTAGE-GATED SODIUM CHANNEL

• Depolarization Stage: The resting membrane suddenly becomes very permeable to sodium ions (stimulus applied causes this permeability) allowing tremendous number of Na⁺ to flow to the interior of the fiber. The normal resting state of -75mV is lost with the potential rising or changing rapidly in the positive direction. This is called depolarization. In large fibers the potential over shoots beyond the zero level and becomes slightly positive (reversal potential). In some smaller fibers as well as in many CNS neurons the potential approaches the zero but does not overshoot or reverse.
• Repolarization Stage: Within a fraction of a second (few 10,000 ths of a second) after the membrane becomes highly permeable for Na⁺ the channels for the Na⁺ close almost as rapidly as they had opened. Then rapid diffusion of K⁺ to the exterior re-establishes the normal negative resting potential. This is called repolarization of the membrane.

Voltage-gated channels of the Cell Membrane

• There are two separate and specific voltage-gated channels, one for Na⁺ and the other for the K^+.
• The principle operator of the stages of action potential ie. causing the depolarization and repolarization of the membrane is the so called voltage-gated Sodium channel.  However, the voltage-gated potassium channel also plays an important role in certain nerve fibers.

The Voltage-gated Sodium Channel

• The channel or the passage has two gates one at the exterior end (opening to the outside of the cell) and the other at the interior end (opening to the inside of the cell). These gates may be referred to as external or internal gates of the channel.  The external gate is known as ‘Activation gate’ and the internal as ‘Inactivation gate’.  The potency of the gates at different stages of an action potential is explained as follows:
  • Resting Stage:  The activation gate is closed and the inactivation gate is opened.  The Na⁺ cannot enter the channel.
  • Activated stage (Depolarization stage): Both the gates are opened and the Na⁺ can freely pass through the channel from the exterior to the interior of the cell.
  • Inactivation Stage (Repolarization stage): The inactivation gate is closed and the Na⁺ cannot enter the channel from the interior of the cell.
    • When the activation gate is opened it is referred to as “activation of the channel” and when the inactivation gate is closed it is referred to as “inactivation of the channel”.

Activation 

• Is effected when the resting membrane potential (-75mV) drops or becomes less negative and reaches a level between -60 to -50mV. Then sudden conformational change in the activation gate flipping it to the open position (Activated state).  Then Na⁺ literally pours into the cell through the channel. At that moment the depolarization process of the membrane begins. The movement of Na⁺ through the membrane is referred to as Sodium permeability of the membrane and it is increased as much as 500 to 5000 fold during activation.

Inactivation 

• The above said drop in negativity otherwise increase in voltage that opens the activation gate also closes the inactivation gate.  However, the closure of the inactivation gate occurs a fraction of a second (few 100,000ths of a second) after activation gate opens ie. The conformational change that flips the inactivation gate to closed state is comparatively a slow process.  Therefore, during the time lapse between the activation and inactivation of the channel which is also a fraction of a second (few 100,000ths of a second) there is passage of Na⁺ to the interior of the cell and at the end the inactivation gate suddenly closes and the Na⁺ no longer pour to the inside of the cell or membrane.  At that moment the repolarization process begins.
• Important characteristics of the inactivation
  • The inactivation gate will not reopen until the disturbed membrane potential returns either to or nearly to the original resting membrane potential level.  Therefore, without the repolarization or nearing completion of repolarization of the fiber it is not possible for the Na⁺ channel to open again.