Actiona potential, properties and clinical corelation.pptx

Actiona potential, properties and clinical corelation.pptx

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  Graded Potential &Action Potential, Conduction & Properties Dr Faiza MBBS (Best Graduate, AIMC Lahore) FCPS Physiology, MHPE (Riphah Int University, Islamabad) ICMT, CHPE, DHPE (STMU) MPH (GC University, Faisalabad) MBA (Virtual University of Pakistan)
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  2 Learning Objectives • DefineAction Potential • Enlist the properties of action potential • Describe the ionic basis of an action potential. • Explain the phases of action potential. • Explain absolute and relative refractory period. • Explain the role of other ions in action potential. • Explain Physiological basis & properties of Graded potential • Contrast between action potential and graded potential • Explain the mechanism of conduction of Nerve impulse in myelinated and unmyelinated nerve fibers. • Elaborate significance of saltatory conduction
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  Membrane Potential
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  Types of GatedChannels • Voltage-gated • Open or close in response to changes in membrane potential. • Chemically gated • Change shape when a specific extracellular messenger binds to a receptor. • Mechanically gated • Respond to stretching or other mechanical deformations. • Thermally gated • Respond to local changes in temperature (heat or cold). • Gated channels contrast with leak channels, which are open all the time.
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  Graded/Electrotonic Potentials Applying subthresholdstimuli of fixed duration leads to a localized depolarising potential change that rises sharply and decays exponentially with time Graded potential α Strength of Stimulus • Most commonly manifest as depolarization due to net entry. • Examples of Graded Potentials: • Postsynaptic potentials • Receptor potentials • End-plate potentials • Pacemaker potentials • Slow-wave potentials
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  Spread of GradedPotentials Localized Depolarization (Triggering the Active Area) Creation of Potential Difference (Between active and inactive regions) Passive Local Current Flow (Ionic migration) Charge Attraction (Positive ions move toward negative adjacent regions) Propagation of Graded Potential (Activation of new membrane areas)
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  Spread of GradedPotentials • Decremental Spread • The magnitude of the potential gradually diminishes as it moves. • Current is lost across the membrane as leaks out through open leak channels. • Signals function only for very short distances (micrometers).
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  Action Potential Rapid changesin the membrane potential that spread rapidly along the nerve fiber membrane
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  Action Potential • RestingStage • The "polarized" membrane at -70 mV
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  Action Potential • DepolarizationStage • Triggered when stimulus reaches threshold (~ -55 mV) • Sudden permeability to Na+ neutralizes internal negativity
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  Action Potential • RepolarizationStage • Na+ channels close • K+ channels open wider
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  Action Potential • Hyperpolarization •K+ channels stay open longer, creating an "undershoot“/hyperpolarization
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  Action Potential • Overshoot •Potential becomes positive in large fibers as Na+ rushes in
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  Stages of theAction Potential • Resting Stage • The "polarized" membrane at -70 mV • Depolarization Stage • Triggered when stimulus reaches threshold (~ -55 mV) • Sudden permeability to Na+ neutralizes internal negativity • Overshoot • Potential becomes positive in large fibers as Na+ rushes in • Repolarization Stage • Na+ channels close • K+ channels open wider • Hyperpolarization • K+ channels stay open longer, creating an "undershoot"
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  Voltage-Gated Sodium ChannelGates • Activation Gate Located near the outside of the channel • Inactivation Gate Located near the inside of the channel
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  Voltage-Gated Sodium ChannelGates • Resting State (-70 mV) • Activation gate is closed • Na+ cannot enter • Activated State • Rising voltage flips the activation gate to "open" • Na+ permeability increases 500- to 5000-fold • Inactivation State • Inactivation gate closes shortly after activation opens
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  Voltage-Gated Sodium ChannelGates • Resting State (-70 mV) • Activation gate is closed • Na+ cannot enter • Activated State • Rising voltage flips the activation gate to "open" • Na+ permeability increases 500- to 5000-fold • Inactivation State • Inactivation gate closes shortly after activation opens
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  Dynamics of SodiumChannel Gating • Fast Response • Activation gate opens almost instantaneously at threshold • Delayed Closure • Inactivation gate closes a few 10,000ths of a second later • Slower Process • Conformational change for inactivation is slower than activation • Repolarization Requirement • Inactivation gate remains closed until resting potential returns • Prevents reopening without first returning to resting state
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  Voltage-Gated Potassium Channel •Resting State • Gate is closed • preventing K+ exit to the exterior • Activation • Triggered as membrane potential rises toward zero • Opens roughly when Na+ channels begin to inactivate • Reduced Na+ entry + increased K+ exit = rapid repolarization • Duration Stays open for the full duration of the positive potential • Recovery • Closes only after the membrane potential returns to negative
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  Conductance Changes DuringAction Potential
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  Positive-Feedback Loop ofInitiation
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  Negative-Feedback Loop ofRepolarization
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  23 Compound Action Potential •Peripheral nerves contain axons of different diameters. • Some axons are myelinated, while others are unmyelinated. • These axons conduct action potentials at different velocities. • External recording therefore produces several peaks rather than a single peak. • Timing of each peak reflects the conduction velocity of a group of axons. • Height of each peak reflects the number of axons in that group. • This combined electrical response is called a compound action potential.
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  24 Compound Action Potential •Clinically, it helps assess nerve function and identify dysfunction in specific groups of axons. • The technique is noninvasive and can be performed using skin surface electrodes.
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  25 Feature Monophasic Action Potential CompoundAction Potential Definition Electrical response recorded from a single nerve or muscle fiber Summed electrical response of many nerve fibers within a nerve trunk Waveform Single deflection, usually in one direction Multiple peaks or phases Conduction velocity Represents one conduction velocity Shows several conduction velocities Clinical use Mainly experimental Used in nerve conduction studies to assess peripheral nerve function
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  Impermeant Anions andCalcium Ions • Internal Anions • Proteins, organic phosphates, and sulfate compounds • Responsible for internal negativity when positive ions are deficient • Calcium Pump • Maintains 10,000-fold gradient (higher outside) • Voltage-Gated Ca2+ Channels, also known as "slow channels“ • Ca2+ provides sustained depolarization in cardiac and smooth muscle
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  Calcium Influence onSodium Channels • Ca 2+ binds to the exterior of Na+ channel proteins • Stabilises by increasing the voltage needed for Na+ gating • Hypocalcemia: • Loss of Na+ channel inhibition leads to hyperexcitability • Muscle Tetany: • Spontaneous nerve discharge when Ca2+ falls 50% below normal • Lethal if respiratory muscles undergo tetanic contraction Ca+2 stabilizes
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  Conduction & Propertiesof Action Potential Action Potential Vs Graded Potential Dr Faiza MBBS (Best Graduate, AIMC Lahore) FCPS Physiology, MHPE (Riphah Int University, Islamabad) ICMT, CHPE, DHPE (STMU) MPH (GC University, Faisalabad) MBA (Virtual University of Pakistan)
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  29 Learning Objectives • Enlistthe properties of action potential. • Explain absolute and relative refractory period. • Contrast between action potential and graded potential • Explain the mechanism of conduction of Nerve impulse in myelinated and unmyelinated nerve fibers. • Elaborate significance of saltatory conduction.
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  30 Characteristics of NerveAction Potential
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  The Threshold forStimulation • Typical threshold in large nerve fibers – 55 mV
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  Principles of NerveConduction • Direction of Propagation • Travels in all directions from the stimulus • Spreads along all branches until the entire membrane depolarizes • All-or-Nothing Principle • Depolarization spreads completely or not at all • Safety Factor • Ratio of action potential to threshold must be >1 • Termination • Spread stops if the generated voltage is insufficient for the next area • stereotypical size and shape
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  All or NoneLaw • an excitable membrane either responds to a triggering event with a maximal action potential that spreads nondecrementally throughout the membrane or does not respond with an action potential at all. • Squeezing the trigger harder does not produce a greater explosion.
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  If Action potentialfollows an “All or None Law”, How strength of stimulus is coded? The strength of a stimulus is coded by the frequency of action potentials.
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  How Ionic Gradientsare Reestablished after Action Potential? Na+ K+ pump reestablishes original concentration differences using ATP
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  Action Potential Plateaus •Membrane does not repolarize immediately • Potential remains near the peak for many milliseconds • Characteristic of heart muscle fibers • Ends when Ca 2+ -Na+ channels close and K+ permeability rises
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  Causes of thePlateau • Fast Channels • Voltage-activated Na+ channels cause the initial spike • Slow Channels • L-type Ca2+ -Na+ channels are slow to open and close • Calcium Influx • Prolonged Ca2+ entry maintains the depolarized state • Delayed K+ Opening • Voltage-gated K+ channels open slower than usual • Combined Effect • Inward Ca2+ flow offsets outward K+ flow initially • Repolarization is delayed until the end of the plateau
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  Initiation at theAxon Hillock Graded potentials (dendrites and cell bodies) Spread toward the axon hillock via local current flow. Summation at axon Hillock (area of highest voltage-gated Na+ channels). Threshold Trigger an "all-or- none" action potential Self-Propagation along the axon without further stimulation
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  Mechanism of Propagation Actionpotential Excites adjacent portions of the membrane Inward Na+ flow local circuit of current flow Positive charges travel 1 to 3 mm along the axon core Local current increases voltage in resting areas to threshold Depolarization → Traveling depolarization Nerve or muscle impulse
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  Saltatory Conduction • Actionpotentials occurs at nodes of Ranvier • Electrical current flows through axoplasm and extracellular fluid • The impulse "jumps" from node to node along the fiber • Velocity is 5 to 50 times faster than in unmyelinated fibers
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  Approximately 0.25 m/sec Upto 100 m/sec Conduction Velocity Unmyelinated Axon Myelinated Axon Type of Nerve fiber Conduction Velocity is also increased by increasing diameter of the fiber
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  Benefits of SaltatoryConduction • Increased Velocity • Enables rapid transmission up to 100 m/sec • Energy Conservation • Only nodes depolarize, reducing total ion loss • Requires ~100 times less energy to restore gradients • Crucial for long-distance signaling in the nervous system
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  Mechanisms of Excitation •Any factor causing Na+ influx can initiate an action potential • Mechanical disturbance • Excites sensory nerve endings in skin • Chemical effects • Neurotransmitters signal between brain neurons • Electrical current • Transmits signals between heart or gut cells
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  Electrical Stimulation Principles NegativeElectrode • Decreases the voltage across the membrane • External negativity moves potential closer to internal negativity • This decrease in voltage allows Na+ channels to open Positive Electrode • Increases the voltage difference (hyperpolarization) • Heightened voltage difference decreases fiber excitability
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  The Absolute RefractoryPeriod • Is the period during which another action potential cannot be elicited, no matter how large the stimulus. • Coincides with almost the entire duration of the action potential • Caused by the inactivation of Na+ channels • second (1 ms)
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  Relative Refractory Period •Follows the absolute refractory period (lasts 2 to 4 ms) • Occurs during the hyperpolarization phase of the potential • A new action potential can be triggered during this time • Requires a much stronger stimulus than a resting neuron • Limits the maximum frequency of nerve impulse transmission
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  Accommodation Prolonged slow rising depolarization - Hyperkalemia Closureof inactivation gates on the Na+ channels. Threshold passed without firing Action potentials Adaptation Occurs when the cell membrane is held at a depolarized level such that the threshold potential is passed without firing an action potential.
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  49 Strength Duration Curve •Rheobase • Rheobase is the minimum strength of electrical stimulus that can excite a nerve fiber when the stimulus is applied for a long duration. • Utilization Time • Utilization time is the minimum duration for which a stimulus of rheobase strength must be applied to excite the nerve fiber. • Chronaxie • Chronaxie is the minimum time required to excite a nerve fiber using a stimulus strength equal to twice the rheobase.
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  Graded vs. ActionPotential Tabulation Feature Graded Potentials Action Potentials Location Primarily dendrites and cell body (soma). Primarily the axon (starts at the hillock). Distance Traveled Short distance (localized). Long distance (entire length of axon). Amplitude (Size) Variable; depends on stimulus strength. All-or-none; always the same magnitude Conduction Type Decremental (signal fades with distance). Non-decremental (strength remains constant). Threshold No threshold required to initiate. Requires reaching a threshold (approx. -55 mV). Channels Involved Ligand-gated or mechanically-gated. Voltage-gated ($Na^+$ and $K^+$ channels). Summation Possible (Temporal and Spatial). Impossible (due to refractory periods). Refractory Period None. Present (Absolute and Relative). Duration Longer (msec to seconds). Brief. Direction Bidirectional flow. Unidirectional (due to refractory period).
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  Clinical Correlations ofNerve Action Potential Degeneration & Regeneration of Nerve Fibres Dr Faiza MBBS (Best Graduate, AIMC Lahore) FCPS Physiology, MHPE (Riphah Int University, Islamabad) ICMT, CHPE, DHPE (STMU) MPH (GC University, Faisalabad) MBA (Virtual University of Pakistan)
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  53 Learning Objectives • Namethe membrane stabilizers. • Explain the physiological basis of action of Local Anesthetics. • Explain the effects of hyperkalemia and Hypokalemia on the Resting Membrane Potential (RMP). • Explain the effects of hyperkalemia and Hypokalemia on the action potential. • Elaborate the effect of hypocalcemia on neuron excitability. • Enlist the types of nerve injury • Explain Wallerian degeneration. • Describe the process of regeneration of nerve fiber. • Describe the causes, features & pathophysiology of Multiple sclerosis, GB syndrome.
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  Effect of Hyperkalemiaon Action Potential Causes of Hyperkalemia • Advanced renal failure or distal tubular acidosis • Adrenal insufficiency and Type 1 diabetes • Dehydration and impaired potassium excretion • ACE inhibitors and Angiotensin II receptor blockers • NSAIDs and potassium-sparing diuretics • Symptoms muscle pain, weakness, numbness, and nausea • Cardiac Impact arrhythmias, cardiac arrest, and death • Hyperkalemic Periodic Paralysis • Resting potential moves from -90 mV to -60 mV • Na Channel Inactivation • Shift prevents action potential generation
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  Effect of Hypokalemiaon Action Potential Causes of Hyperkalemia • Increased losses • Ion Shifts to intracellular space • Bartter syndrome and Gitelman syndrome • Cushing syndrome and diabetic ketoacidosis • Prolonged use of -wasting diuretics • General Symptoms weakness, fatigue, and muscle cramping • Gastrointestinal constipation due to smooth muscle effects • Psychological potential for depression or psychosis • Cardiac Rhythmicity palpitations and rhythm disturbances • Severe Levels (<2.5 mEq/L) bradycardia and tachycardia • Hyperpolarization • Decreased excitability
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  Membrane Stabilizers • Factorsthat decrease excitability by reducing permeability • Calcium Ions • High extracellular Ca2+ stabilizes the membrane • Ca2+ reduces Na+ permeability, making excitation harder • Prevents spontaneous or accidental nerve discharge • Essential for maintaining appropriate neurological sensitivity
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  Calcium Influence onSodium Channels • Ca 2+ binds to the exterior of Na+ channel proteins • Stabilises by increasing the voltage needed for Na+ gating • Hypocalcemia • Loss of Na+ channel inhibition leads to hyperexcitability • Muscle Tetany • Spontaneous nerve discharge when Ca2+ falls 50% below normal • Lethal if respiratory muscles undergo tetanic contraction Ca+2 stabilizes
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  Local Anaesthetics • Mechanism •Bind directly to the activation gates of Na+ channels • Make it significantly more difficult for Na+ gates to open • Reduce the "safety factor" of the nerve impulse to below 1.0 • When safety factor is < 1.0, the impulse fails to propagate • Results in the temporary loss of signal transmission (numbness) • Classification & Progression: • Two major categories ester-linked and amide-linked agents • Cocaine first identified and only naturally occurring local anesthetic • Order of Blockade Nociceptive (C fibers) are most sensitive • Sequential Loss pain → temperature → touch → deep pressure → motor
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  Multiple Sclerosis (MS) Autoimmunedisease attacking myelin in the Central Nervous System Pathophysiology Environmental triggers Epstein-Barr, measles, or influenza viruses Immune system attacks myelin, causing inflammation Ionic leakage, hyperpolarization, and conduction failure Presentation paraparesis, paresthesia, urinary incontinence, and heat intolerance Optic Neuritis blurred vision, color change, and central scotoma Bulbar Symptoms dysarthria (speech) and dysphagia (swallowing) Variable Progression relapsing-remitting or progressive forms Diagnosis CSF Analysis detects oligoclonal bands MRI visualizes sclerotic plaques, often in periventricular regions Treatement Corticosteroids β-interferons (suppress immune response) Natalizumab (Immune Barriers) Rituximab and Ocrelizumab (target CD20 markers) Fingolimod (Lymphocyte Sequestration)
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  Guillain–Barré Syndrome • Autoimmunereaction to peripheral myelin proteins (P0 and PMP22) • Peripheral demyelinating neuropathy • Leads to delayed or blocked conduction in affected axons • MS affects the CNS, GBS affects the PNS • Results in muscle weakness and sensory changes
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  • Blocks Na+channels when applied to the outside • Specifically affects Na+ activation gates Tetrodotoxin • Blocks K+ channels when aapplied to the interior of the nerve fibre Tetraethylammonium • Allows investigators to study one channel type in isolation • Confirms separate roles of Na+ and K+ conductance Research Utility
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  Fiber Sensitivity toPressure and Hypoxia
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  63 Nerve Degeneration • Structuraland functional breakdown of a nerve fiber following injury or disease. • Etiologies: Trauma (crush/laceration), Ischemia, Infections (leprosy), Metabolic disorders (diabetes), and Toxins. • Sunderland’s Classification (Severity levels): • Neuropraxia: Temporary conduction block; no structural damage. • Axonotmesis: Axon damaged; connective tissue sheaths remain intact. • Neurotmesis: Complete severance of both the axon and connective tissue
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  64 Wallerian Degeneration • Structuralchanges happening distal to the site of injury. • Events: • The distal axon swells and fragments into debris within days. • The myelin sheath disintegrates into ellipsoids. • Macrophages and Schwann cells rapidly clear debris via phagocytosis.
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  65 Nerve Regeneration • Macrophagesand Schwann cells rapidly clear debris via phagocytosis. • Remaining Schwann cells proliferate to form regeneration tubes (guides for new fibers). • Denervated distal stumps and Schwann cells increase neurotrophin production to attract the growing axon tip. • Perineurium Inhibitory molecules ensure regenerating axons grow in correct trajectory • Axonal sprouting occurs from the proximal stump • Amoeboid Movement of axon tip to move forward within the Schwann cell column • Functional Recovery Return of sensation and movement, though fine control may vary
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  66
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  67 Regeneration Dynamics –PNS vs. CNS • PNS: • Schwann cells promote growth by releasing neurotrophins and forming physical guidance tubes. • NgCAM/L1: Adhesion molecules in the PNS that promote growth along membranes. • Successful regeneration in the PNS typically occurs at 1–3 mm/day • CNS: • Oligodendrocytes synthesize inhibitory proteins (e.g., Nogo) and do not support repair. • Barriers: astrocytic proliferation, activation of microglia, scar formation, inflammation, and invasion of immune cells
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  Neurotrophins • Proteins essentialfor the survival, development, and growth of neurons. • Production Sources: • Astrocytes (common in the CNS). • Target structures (e.g., muscles innervated by the neuron). • Neurons themselves. • Core Function: • Internalized at nerve endings and transported via retrograde transport to the cell body to foster protein production. • Anterograde Role: • Some are transported to nerve endings to maintain the integrity of the postsynaptic neuron.
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  Types of Neurotrophins NeurotrophinPrimary Target / Function NGF Skin nociceptive neurons; sympathetic neurons. NT-3 Proprioceptor neurons (muscle spindles); mechanoreceptors; sympathetic neurons. NT-4/5 Neurons innervating hair follicles. BDNF Vestibular ganglia; involved in long-term potentiation (LTP); can depolarize neurons.
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  Other Neurotrophic Factors •CNTF (Ciliary Neurotrophic Factor): • Produced by Schwann cells and astrocytes. • Promotes survival of damaged/embryonic spinal cord neurons. • GDNF (Glial Cell Line–Derived Neurotrophic Factor): • Maintains midbrain dopaminergic neurons. • Prevents apoptosis of spinal motor neurons. • LIF (Leukemia Inhibitory Factor): • Enhances neuronal growth. • Additional Factors: • Neurons also respond to IGF-I, TGF, FGF, and PDGF.
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  71 Mixed Nerve Injuries •Aberrant Regeneration: • When a mixed nerve (containing sensory, motor, and autonomic fibers) is severed, regenerating axons may mistakenly enter the wrong endoneural tubes. • Misdirected Impulses: • This structural mix-up leads to axons targeting inappropriate peripheral end organs, resulting in abnormal physiological responses.
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  72 Mixed Nerve Injuries •Frey's Syndrome: • Aberrant regeneration following an injury to the auriculotemporal nerve. • While eating, the patient experiences ipsilateral cheek flushing (redness), heat, pain, and sweating, along with hyperaesthesia in front of and above the ear. • Mechanism: • Severed secretory axons intended for the salivary glands grow into endoneural tubes supplying cutaneous receptors and sympathetic sweat glands. • A normal physiological stimulus for salivary secretion mistakenly triggers cutaneous hyperaesthesia, sweating, and flushing in the affected area.
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  73 Neuroma Formation • Successfulregeneration is hindered if the gap between the proximal and distal stumps of a completely severed nerve is too wide. • Regeneration also fails if the gap becomes filled with proliferating fibrous tissue or bulging adjacent muscular tissue. • Neuroma Development: Instead of crossing the gap, growing axonal sprouts enter the surrounding connective tissue and form a painful, tangled mass known as a neuroma.
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  74 Feature Entrapment SyndromesRadiculopathy Origin of Compression Peripheral nerve, further down the limb (distal). Nerve root, right at the spinal cord (proximal). Symptom Distribution Localized specifically to the isolated territory of the affected peripheral nerve. Follows a specific dermatome (sensory area) and myotome (muscle group) path down the limb. Pain Characteristic s Aching, burning, or tingling usually starting at or below the pinch point. Neck/back pain is absent. "Shooting" or "electrical" pain radiating from the spine down the arm or leg. Often accompanied by neck or back pain. Example Condition Carpal Tunnel Syndrome (Median Nerve compression at the wrist). Cervical Radiculopathy (C6 nerve root compression at the neck due to a herniated disc).
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  Thank You References: • Guyton,A. C., & Hall, J. E. (2021). Textbook of Medical Physiology (15th ed., Chapter 5: Membrane Potentials and Action Potentials). Philadelphia, PA: Elsevier. • Barrett, K. E., Barman, S. M., Brooks, H. L., & Yuan, J. X.-J. (2019). Ganong’s Review of Medical Physiology (26th ed., Chapter 4: Excitable Tissue: Nerve). New York, NY: McGraw-Hill Education. • Sherwood, L. (2015). Human Physiology: From Cells to Systems (9th ed., Chapter 4: Principles of Neural and Hormonal Communication ). Boston, MA: Cengage Learning.