Resting Membrane Potential of Nerve: Ionic Mechanisms and Functional Significance Explained

Resting Membrane Potential of Nerve: Ionic Mechanisms and Functional Significance Explained

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  RESTING MEMBRANE POTENTIAL OFNERVE : IONIC MECHANISMS AND FUNCTIONAL SIGNIFICANCE Dr.Hyma J Junior Resident Department of Physiology AIIMS Deoghar Moderator : Dr.Anita Kumari
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  OBJECTIVES 1.Introduction 2.History 3.Factors affecting RMP ●Selective permeability of the cell membrane to various ions ● Gibbs–Donnan equilibrium ● Nernst equation ● Goldman-Hodgkin equation ● Na /K Pump ⁺ ⁺ 4.Measurement of Membrane Potential 5.Applied aspects 6.Summary 7.References
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  Electrical Properties ofNerve Fibres 1. Excitability ● Ability of nerve fibre to respond to a stimulus by generating an action potential ● Stimuli can be: ○ Mechanical ○ Thermal ○ Chemical ○ Electrical (most commonly used experimentally) ● Requires a threshold stimulus to trigger response 2. Conductivity ● Ability to propagate the action potential along the entire length of the nerve fibre without decrement
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  Resting Membrane Potential(RMP) ● Resting membrane potential is the potential difference across the cell membrane when the cell is at rest ● Outside is taken as 0 mV (reference) ● Inside is negative relative to outside ● RMP provides the baseline electrical state ● Necessary for: ○ Excitability of neurons ○ Generation of action potential ● Without RMP → no signal transmission
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  History
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  Factors Contributing toMembrane Potential Membrane potential is mainly due to distribution of ions across the cell membrane, which results mainly from the selective permeability of the cell membrane to various ions at rest. However, membrane potential is influenced by various forces affecting the ion distribution. 1. Selective permeability of the cell membrane to various ions 2. Gibbs–Donnan equilibrium 3. Nernst equation 4. Goldman-Hodgkin equation 5. Na /K Pump ⁺ ⁺
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  Selective permeability ofthe cell membrane to various ions Factors Affecting Permeability ● Molecular weight ● Hydrated ionic radius (more important) ● Charge of ion ● Lipid solubility (for non-ions) Smaller hydrated radius = higher permeability Hydrated Radius Concept ● Ions attract water molecules → form hydrated shell ● Effective size = hydrated radius, not atomic size ● Determines ease of passage through membrane channels
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  Permeability Order Even thoughmany ions are diffusible:K > Cl > Na ⁺ ⁻ ⁺ ● K has: ⁺ ○ Higher molecular weight than Na⁺ ○ BUT much smaller hydrated radius Therefore: ● K permeability is 500–1000 times greater than Na ⁺ ⁺ Why is K More Permeable? ⁺ ● Smaller hydrated radius ● More leak channels for K⁺ ● Easier movement across membrane Impermeable Substances ● Intracellular proteins ● Organic phosphates These are: ● Large in size ● Highly charged ● Cannot cross membrane
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  Ion Distribution AcrossMembrane ● Unequal distribution of ions is the basis of RMP: ○ Outside: Na high, K low ⁺ ⁺ ○ Inside: K high, Na low + negatively ⁺ ⁺ charged proteins ● This creates a concentration gradient
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  Gibbs–Donnan Membrane Equilibrium Whentwo ionic solutions are separated by a semipermeable membrane At equilibrium: ○ Each solution remains electrically neutral ○ Distribution of ions follows specific rules Electroneutrality ○ Total cations = Total anions in each compartment Donnan Product Rule ○ Product of diffusible ions is equal on both sides Example (Without Non-diffusible Ions) ● Two compartments A and B ● Contain: Na and Cl ⁺ ⁻ ● Both ions are freely diffusible Equal distribution of ions on both sides Donnan Equilibrium Condition ● Product remains constant: (Na+)A×(Cl−)A=(Na+)B×(Cl−)B Ensures balanced ionic distribution
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  Introduction of Non-diffusibleIon (X ) ⁻ ● Add non-diffusible anion (X ) ⁻ to side A ● X⁻ cannot cross membrane : Effect on Ion Distribution ● To maintain electroneutrality: In B: (Na+)B=(Cl−)B Redistribution of Diffusible Ions ● Cl moves to side B ⁻ ● Na moves to side A ⁺ Final outcome: ● (Na+)A>(Na+)B ● (Cl−)A<(Cl−)B Donnan Product Maintained ● Even after redistribution: (Na+)A×(Cl−)A=(Na+)B×(Cl−)B Product rule still holds
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  Concept of Equilibrium(Nernst) Potential ● When an ion is allowed to move freely, it moves due to concentration gradient ● As it moves, it creates an electrical gradient ● The point where both forces balance = Equilibrium potential ● At this point → no net ion movement
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  Assumption in Diagram ●Membrane is permeable only to K⁺ ● So only K movement is considered in generating potential ⁺ Chemical Gradient of K⁺ ● K concentration is ⁺ high inside ● So K tends to ⁺ diffuse out of the cell ● This is driven by concentration (chemical) gradient Electrical Gradient Development ● As K leaves: ⁺ ○ Positive charges go out ○ Inside becomes negatively charged ● This creates an electrical gradient ● Now electrical force pulls K back inside ⁺ Michael-Titus AT, Shortland PJ. The Nervous System. Edinburgh: Elsevier; 2023. p. 33-52.
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  Electrochemical Gradient ● Twoopposing forces act on K : ⁺ ○ Chemical gradient → pushes K out ⁺ ○ Electrical gradient → pulls K in ⁺ ● The balance of these = electrochemical equilibrium Seifter JL, Walsh EC, Sloane DE. Integrated Physiology and Pathophysiology. Philadelphia: Elsevier; 2022. p. 15-29. Diffusion Potential ● Movement of K creates a ⁺ potential difference across membrane ● This is called diffusion potential
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  Equilibrium State (NernstPotential) ● At around –94 mV (for K ) ⁺ : ○ Outward chemical force = inward electrical force ○ No net movement of K⁺ ● This is called: ○ Equilibrium potential (E ) ₖ ○ Nernst potential
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  Nernst Equation ● TheNernst equation calculates equilibrium potential of an ion ● Formula: ● Where: ○ E = equilibrium potential (mV) ○ z = valency of ion ○ 61 = constant at 37°C
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  Assumption :Membrane ispermeable only to Na⁺ Na Concentration Gradient ⁺ ● Na is ⁺ high outside, low inside ● So Na tends to ⁺ diffuse into the cell Electrical Changes ● As Na enters: ⁺ ○ Positive charge enters cell ○ Inside becomes positive ● This creates an electrical gradient opposing further Na entry ⁺ Na Equilibrium Potential (E ) ⁺ ₙₐ ENa=+61 mV ● At +61 mV: ○ Inward chemical force = outward electrical force ○ No net movement of Na⁺ Seifter JL, Walsh EC, Sloane DE. Integrated Physiology and Pathophysiology. Philadelphia: Elsevier; 2022. p. 15-29.
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  Hall JE, HallME, Vaz M, Kurpad A, Raj T. Guyton and Hall Textbook of Medical Physiology. 3rd South Asia ed. Noida: Elsevier India; 2020. p. 61-64.
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  When Membrane isPermeable to Multiple Ions ● In real cells, membrane is permeable to more than one ion (K , Na , Cl ) ⁺ ⁺ ⁻ ● Therefore, membrane potential depends on combined effect of all ions Factors Determining Diffusion Potential Diffusion potential depends on: 1. Charge (valency, z) of ion 2. Concentration gradient (inside vs outside) 3. Permeability (P) of membrane to each ion ● Nernst equation considers one ion only ● Real situation needs multiple ion consideration
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  Goldman-Hodgkin-Katz Equation ​ ​ ● Takesinto account: ○ Multiple ions ○ Relative permeability ● Gives actual membrane potential ● Each ion contributes based on its: ○ Concentration ○ Permeability ● Ion with highest permeability dominates
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  Why K DominatesRMP ⁺ ● Membrane is much more permeable to K than Na ⁺ ⁺ ● Therefore: ○ RMP is closer to E (–94 mV) ₖ ○ But slightly less negative → ~ –70 mV
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  Role of Na/K Pump ⁺ ⁺ ● Pump action: ○ 3 Na out ⁺ ○ 2 K in ⁺ ● Net effect: ○ Loss of one positive charge → makes inside more negative Pump Contribution ● Adds about –4 mV to membrane potential ● So: ○ → becomes ≈ –70 mV Hall JE, Hall ME, Vaz M, Kurpad A, Raj T. Guyton and Hall Textbook of Medical Physiology. 3rd South Asia ed. Noida: Elsevier India; 2020. p. 61-64.
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  Ionic Basis ofResting Membrane Potential (RMP) Resting membrane potential (~ –70 mV) is mainly determined by K diffusion ⁺ , with a small contribution from Na⁺ and the Na /K pump ⁺ ⁺ . A. Potassium (K ) Distribution ⁺ ● Inside cell: 140 mEq/L, Outside: 4 mEq/L ● K diffuses ⁺ outward through leak channels ● Leaves behind negative charges → generates –94 mV ● Major contributor to RMP B. Sodium (Na ) Distribution ⁺ ● Outside: 142 mEq/L, Inside: 14 mEq/L ● Na tends to diffuse ⁺ into the cell ● Would create +61 mV, but membrane is less permeable to Na⁺ ● Hence, Na has ⁺ minor influence on RMP C. Combined Effect + Na /K Pump ⁺ ⁺ ● K efflux > Na influx → net ⁺ ⁺ negative inside ● Na /K ATPase ⁺ ⁺ : ○ Pumps 3 Na out ⁺ , 2 K in ⁺ ○ Maintains gradients and adds slight negativity ● Final RMP ≈ –70 mV Hall JE, Hall ME, Vaz M, Kurpad A, Raj T. Guyton and Hall Textbook of Medical Physiology. 3rd South Asia ed. Noida: Elsevier India; 2020. p. 61-64.
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  Mulroney SE, MyersAK. Netter's Essential Physiology. Philadelphia: Elsevier; 2025. p. 24-47.
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  Measurement of MembranePotential Done using a microelectrode (glass pipette with electrolyte) Inserted inside the cell Reference (indifferent electrode) placed outside Potential difference measured using: ○ Voltmeter / Oscilloscope What Happens During Measurement ● Outside cell → 0 mV (reference) ● When electrode enters cell: ○ Sudden drop to –90 mV ● Inside remains constant ● On exiting → returns to 0 mV Hall JE, Hall ME, Vaz M, Kurpad A, Raj T. Guyton and Hall Textbook of Medical Physiology. 3rd South Asia ed. Noida: Elsevier India; 2020. p. 61-64.
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  Cathode Ray Oscilloscope(CRO) An almost inertialess instrument used to record and measure rapid electrical events in living tissues (e.g., nerve action potentials) Main Components ● Cathode (Electron Gun): Emits electrons when connected to anode ● Fluorescent Screen: Converts electron beam into visible light ● Deflection Plates: ○ Horizontal Plates (X-axis): ■ Connected to sweep generator ■ Apply sawtooth voltage ■ Produces horizontal movement of beam → time axis ○ Vertical Plates (Y-axis): ■ Connected to recording electrodes via amplifier ■ Cause vertical deflection based on voltage changes Working Principle ● Electron beam strikes fluorescent screen → produces glowing trace ● Horizontal sweep shows time progression ● Vertical deflection represents voltage changes ● Action potential appears as vertical deflection on moving trace Khurana I, Khurana A, Kowlgi NG. Textbook of Medical Physiology. 4th ed. New Delhi: Elsevier; 2024.
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  Mtui E, GruenerG, Dockery P. Fitzgerald's Clinical Neuroanatomy and Neuroscience. Philadelphia: Elsevier; 2021. p. 79-88.
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  Patch clamp technique Principle: ●Measures ionic currents through single ion channels using a glass micropipette. ● Forms a high-resistance seal (gigaseal) with the cell membrane. Configurations: ● Cell-attached: Mild suction → tight seal; records channel activity in intact membrane ● Whole-cell: Strong suction → membrane ruptures; pipette accesses cytoplasm ● Inside-out patch: Membrane pulled away → cytoplasmic side exposed ● Outside-out patch: Membrane reseals → extracellular side exposed Importance: Allows study of channel properties, gating, and drug effects at single-channel level
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  Voltage clamp technique Principle: ●Maintains membrane potential constant while measuring ionic currents ● Uses feedback amplifier system Components: ● Voltage electrode: Measures membrane potential ● Current electrode: Injects current to maintain set voltage ● Amplifier: Adjusts current to “clamp” voltage Working: ● Any ion movement → change in voltage ● Amplifier injects opposite current → keeps voltage constant ● Measured current = ionic current across membrane Significance: Essential for studying Na , K currents ⁺ ⁺ and action potential mechanisms
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  APPLIED ASPECTS
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  Electrolyte Disorders ● Hyperkalemia(↑K outside): ⁺ RMP becomes less negative → increased excitability → may lead to arrhythmias ● Hypokalemia (↓K outside): ⁺ RMP becomes more negative → decreased excitability → muscle weakness/paralysis Action of local anaesthetics ● Lidocaine ● Bupivacaine ● They block voltage gated Na channels : action potential cannot be generated, nerve conduction stops. Role of Na+/K+ pump inhibition ● Ouabain -alters RMP and may cause cell swelling and dysfunction
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  REFERENCES 1. Hall JE,Hall ME, Vaz M, Kurpad A, Raj T. Guyton and Hall Textbook of Medical Physiology. 3rd South Asia ed. Noida. Chapter: Nerve Membrane, Action Potential & Excitation of Nerves. 2. Barrett KE, Barman SM, Brooks HL, Yuan JXJ. Ganong’s Review of Medical Physiology. 27th ed. New York: McGraw Hill; 2025. Section: Excitable Tissue: Nerve. 3. Khurana I, Khurana A, Kowlgi NG. Textbook of Medical Physiology. 4th ed. New Delhi: Elsevier; 2024. 4. Koeppen BM, Stanton BA. Berne and Levy Physiology. 8th ed. Philadelphia: Elsevier; 2018. Topic: Cellular Neurophysiology. 5. Costanzo LS. Physiology. 7th ed. Philadelphia: Elsevier; 2023. Chapter: Neurophysiology. 6. Mtui E, Gruener G, Dockery P. Fitzgerald's Clinical Neuroanatomy and Neuroscience. 8th ed. Philadelphia: Elsevier; 2021. p. 79-88. 7. Mulroney SE, Myers AK. Netter's Essential Physiology. 3rd ed. Philadelphia: Elsevier; 2025. p. 24-47. 8. Seifter JL, Walsh EC, Sloane DE. Integrated Physiology and Pathophysiology. 2nd ed. Philadelphia: Wolters Kluwer; 2022. p. 15-29. 9. Michael-Titus AT, Shortland PJ. The Nervous System. 2nd ed. Edinburgh: Elsevier; 2023. p. 33-52.
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