Previouse Notes:

https://mednotesbyrazaullah.blogspot.com/2026/08/resting-membrane-potential-overview.html

Voltage-gated Sodium Channel Mechanism

The voltage-gated sodium channel is described as the primary molecular trigger for generating action potentials in excitable tissues. This membrane protein possesses two distinct gates: an activation gate near the outer opening of the channel and an inactivation gate near the inner opening. In the resting state (at -90{ mV}), the activation gate remains tightly closed, preventing any inward flow of sodium ions, while the inactivation gate stays wide open.

When a stimulus depolarizes the cell membrane toward threshold (around -65{ mV}), the sudden shift in electrical voltage causes a conformational change in the protein structure that snaps the activation gate open. Sodium ions rush into the cell down their steep electrochemical gradient, causing rapid depolarization.Within a few ten-thousandths of a second, the same voltage shift triggers the slower-moving inactivation gate to close. Once inactivated, sodium influx stops completely, and the channel cannot reopen until the membrane potential fully repolarizes back near its resting -90{ mV} baseline.

Activation Phase:

• Membrane potential becomes less negative toward zero.
• Reaches threshold between -70 mV and -50mV.
• The activation gate flips completely open.
• Sodium ions pour inward rapidly.
• Sodium permeability increases 500-fold to 5000-fold.

Inactivation Phase:

• Voltage increase also triggers inactivation gate closure.
• Inactivation gate closes slightly slower than activation gate.
• Closes a few ten-thousandths of a second later.
• Stops sodium entry into the cell membrane.
• Initiates membrane repolarization process.
• Reopening requires returning to resting membrane potential.

Voltage-Gated Potassium Channel

Channel Activation:

• The gate remains closed during the resting state.
• Voltage rise toward zero opens the gate.
• Opens with a slight time delay.
• Opens as sodium channels begin inactivating.
• Increased outward potassium diffusion speeds repolarization.
• Restores resting membrane potential within milliseconds.

The Voltage Clamp Research Method

Experimental Setup:

• Invented by Hodgkin and Huxley (Nobel Prize winners).
• Measures ion flow through specific channel types.
• Inserters insert two micro electrodes into nerve fiber.
• One electrode measures membrane potential voltage.
• The second electrode injects electrical current.
• Automatically holds voltage at set experimental level.

Channel Blocking Agents:

• Tetrodotoxin blocks sodium channels externally.
• Tetraethylammonium ions block potassium channels internally.

Conductance Changes:

• Sodium channels open instantly upon voltage increase.
• Sodium channels close automatically within one millisecond.
• Potassium channels open slowly after sodium channels close.
• Potassium channels stay open during positive potential.
• Potassium channels close when potential returns negative.

Summary of Action Potential Events

Conductance Ratios:

• Resting potassium conductance exceeds sodium by 50–100 times.
• Onset increases sodium conductance up to 5000-fold.
• Early action potential sodium/potassium ratio increases 1000-fold.
• Inflow of sodium creates positive internal potential.
• Inactivation closes sodium channels within fraction millisecond.
• Delayed potassium channels open to increase outward flow.
• Shift toward potassium conductance rapidly restores baselines.

Roles of Other Ions During Action Potential

Impermeant Negatively Charged Anions:

• Impermeant anions remain trapped inside the axon.
• Include intracellular proteins, organic phosphates, and sulfates.
• Cannot pass through membrane channels.
• Create internal negativity when a positive ions deficit exists.

Calcium Ions and Calcium Pumps:

• Calcium pumps transport Ca^{2+} from inside to outside.
• Maintains 10,000-fold calcium concentration gradient.
• Intracellular Ca^{2+} concentration is 10^ -7 M
• Extracellular Ca^{2+} concentration is 10^{-3}{ M}.

Voltage-Gated Calcium Channels:

• Permeability of calcium is 1000-fold greater than sodium.
• Depolarization opens channels, causing calcium influx.
• Gating is slow, taking 10 to 20 times longer than sodium.
• Known as slow channels compared to fast sodium channels.
• Provide sustained depolarization in target cells.
• Abundant in cardiac muscle and smooth muscle.
• Drive smooth muscle action potentials lacking fast sodium channels.

Effect of Calcium Deficit on Sodium Channels:

• Extracellular Ca^{2+} binds exterior surfaces of sodium channels.
• Calcium positive charges alter sodium channel electrical state.
• Low Ca^{2+} activates sodium channels at lower voltages.
• Lowers threshold, making nerve fibers highly excitable.
• A 50% Ca^{2+} drop causes spontaneous nerve discharge.
• Causes muscle tetany, potentially lethal via respiratory muscles.

Initiation of the Action Potential

Positive-Feedback Cycle:

• Undisturbed nerve membrane maintains resting potential.
• Initial voltage rise opens voltage-gated sodium channels.
• Inflowing sodium increases voltage, opening more channels.
• Positive-feedback cycle activates all voltage-gated sodium channels.
• Rising potential subsequently closes sodium and opens potassium channels.

Threshold for Stimulation:

• Requires sodium influx to exceed potassium efflux.
• Requires sudden voltage rise of 15\ mV} to 30\{ mV}.
• Shift from -90\{ mV} to -65\{ mV} initiates action potential.
• -65\ mV} level is the threshold for stimulation.