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Propagation of Nerve Impulse & Physiology of Muscle Contraction

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PART I: PROPAGATION OF THE NERVE IMPULSE

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1. The Resting Membrane Potential

• The Na⁺-K⁺ ATPase pump (electrogenic - pumps 3 Na⁺ out for every 2 K⁺ in)
• Selective K⁺ leak channels (K⁺ diffuses out along its concentration gradient)
• Large intracellular organic anions that cannot cross the membrane

In skeletal muscle fibers, the resting membrane potential is slightly more negative: -80 to -90 mV.

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2. The Action Potential - Ionic Basis

Successive Phases:

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3. Voltage-Gated Sodium and Potassium Channels

1. Resting state (-70 mV): Activation gate closed, inactivation gate open → no Na⁺ flow
2. Activated state (threshold reached): Activation gate opens rapidly → Na⁺ rushes in (500-5000x increase in permeability). This occurs within a fraction of a millisecond.
3. Inactivated state (a few 10,000ths of a second after opening): Inactivation gate closes → Na⁺ flow stops. The inactivation gate will NOT reopen until membrane potential returns to near -70 mV (basis of absolute refractory period).

• Has a single gate
• Opens slowly when membrane potential rises (delayed ~1 ms relative to Na⁺ channel opening)
• Opens maximally just as Na⁺ channels are inactivating → accelerates repolarization
• Slow to close → produces the afterhyperpolarization

"Any event that causes enough initial rise in the membrane potential from -70 mV toward zero causes many voltage-gated sodium channels to begin opening. This allows rapid inflow of sodium ions, which causes a further rise in the membrane potential, opening still more channels - a positive-feedback cycle." - Guyton & Hall

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4. Propagation of the Action Potential

1. At the site of excitation, Na⁺ rushes in → inside becomes positive
2. This creates an electrical potential difference between the active zone (+) and adjacent resting zone (-) on both the intracellular and extracellular surfaces
3. Local ionic currents flow: positive charges flow intracellularly from active → adjacent resting zone; extracellularly from resting → active zone
4. These currents depolarize adjacent membrane to threshold → new action potential generated
5. Process repeats continuously → the impulse propagates along the entire fiber

• The action potential travels in all directions away from the point of stimulation
• All-or-Nothing Principle: once threshold is reached, the action potential either fully propagates or does not propagate at all
• The safety factor for propagation must always be >1 (ratio of action potential voltage to threshold)
• The depolarized zone behind the traveling impulse is in its refractory period and cannot be re-excited → ensures unidirectional propagation in neurons (since axons are typically stimulated at one end)

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5. Refractory Periods

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6. Myelinated Fibers and Saltatory Conduction

• The action potential "jumps" from one node of Ranvier to the next
• Local currents flow through the low-resistance axoplasm from an active node to the next node, depolarizing it to threshold
• The impulse "skips" over the myelinated internodal segments

1. Speed: Conduction velocity in large myelinated fibers = 70-120 m/sec vs. ~0.5-2 m/sec in unmyelinated fibers (C fibers)
2. Energy efficiency: Na⁺-K⁺ pumps only need to restore gradients at nodes (much less membrane area) → far less ATP consumed
3. Node-to-node jumping makes it much faster than continuous conduction

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7. Factors Affecting Conduction Velocity

• Fiber diameter: Larger diameter → lower axial resistance → faster conduction
• Myelination: Saltatory conduction dramatically increases velocity
• Temperature: Higher temperature → faster conduction (local anesthetics work partly by cooling)
• Hypocalcemia: Increases excitability (Ca²⁺ stabilizes Na⁺ channel inactivation gates; when Ca²⁺ falls, channels open more readily → spontaneous discharges, tetany)

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PART II: PHYSIOLOGY OF MUSCLE CONTRACTION

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1. Structure of Skeletal Muscle - From Gross to Molecular

Muscle → Muscle Fascicle → Muscle Fiber (cell) → Myofibril → Sarcomere → Thick (myosin) & Thin (actin) Filaments

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2. Molecular Structure of Contractile Proteins

• MW ~480,000; composed of 6 polypeptide chains: 2 heavy chains + 4 light chains
• Heavy chains coiled together forming a tail; each end has a globular head (S1 fragment)
• The myosin head contains: (a) an actin-binding site and (b) an ATPase site that hydrolyzes ATP to generate the power stroke
• ~300 myosin molecules aggregate tail-to-tail to form one thick filament; heads project outward as cross-bridges

• F-actin: double-stranded helix of G-actin monomers (~1 μm long)
• Active sites on each G-actin monomer interact with myosin heads
• Tropomyosin: coiled-coil protein lying in the groove of the actin helix; in resting state covers the active sites on actin, blocking myosin binding
• Troponin complex: attached to tropomyosin at regular intervals; 3 subunits:
  • Troponin I (inhibitory): binds actin strongly
  • Troponin T: binds tropomyosin
  • Troponin C: binds Ca²⁺ (up to 4 ions per molecule) - the critical regulatory subunit

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3. The Neuromuscular Junction (NMJ)

1. Motor nerve AP arrives at the motor nerve terminal (presynaptic)
2. Depolarization opens voltage-gated Ca²⁺ channels at the terminal
3. Ca²⁺ influx triggers exocytosis of acetylcholine (ACh) from synaptic vesicles
4. ACh diffuses across the synaptic cleft (~20-30 nm)
5. ACh binds to nicotinic ACh receptors (ligand-gated ion channels) on the motor end plate (postsynaptic membrane)
6. Opening of these channels → large Na⁺ influx (and some K⁺ efflux) → end-plate potential (EPP)
7. EPP depolarizes adjacent sarcolemma to threshold → generates a muscle action potential
8. Acetylcholinesterase in the synaptic cleft rapidly degrades ACh → termination of signal

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4. Excitation-Contraction (E-C) Coupling

1. Muscle AP propagates along the sarcolemma
2. AP travels deep into the fiber via transverse (T) tubules - which are invaginations of the sarcolemma open to extracellular fluid, penetrating to each myofibril
3. T-tubule depolarization activates DHP receptors (dihydropyridine receptors / voltage sensors) in the T-tubule membrane
4. DHP receptors mechanically couple to Ryanodine receptors (RyR / Ca²⁺-release channels) on the terminal cisternae of the sarcoplasmic reticulum (SR)
5. RyR channels open → massive Ca²⁺ release from SR into the sarcoplasm (sarcoplasmic Ca²⁺ rises from 10⁻⁷ M to 10⁻⁵ M)
6. Ca²⁺ binds to Troponin C → conformational change → tropomyosin shifts deeper into the actin groove → active sites on actin are exposed
7. Myosin heads can now bind to actin → cross-bridge cycling begins → contraction

• Ca²⁺ is actively pumped back into SR by SERCA (SR Ca²⁺-ATPase)
• Ca²⁺ falls below threshold → Troponin C releases Ca²⁺ → tropomyosin returns to blocking position → active sites concealed → cross-bridges detach → muscle relaxes

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5. The Sliding Filament Theory of Contraction

• Myosin and actin filaments do not shorten - they maintain constant length
• Contraction occurs because actin filaments slide past myosin filaments, pulling Z-disks toward each other
• Force is generated by cross-bridge interactions between myosin heads and actin

• A band: constant (myosin length unchanged)
• I band: decreases (actin now overlaps more with myosin)
• H zone: decreases or disappears (actin tips overlap)
• Sarcomere length: decreases (Z-disks approximate)

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6. The Cross-Bridge Cycle (Walk-Along Mechanism)

Each cross-bridge cycle moves the actin filament ~10 nanometers and uses 1 ATP molecule. Multiple cycles per second allow sustained, graded contraction.

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7. Role of Calcium in Muscle Contraction

• In resting muscle: tropomyosin covers active sites → no actin-myosin interaction possible
• Ca²⁺ (from SR) binds Troponin C → conformational change in troponin complex → tugs tropomyosin deeper into actin groove → active sites exposed
• Cross-bridge cycling can now proceed

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8. Sources of Energy for Muscle Contraction

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9. Types of Muscle Contraction

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10. Length-Tension Relationship

• Optimal sarcomere length (~2.0-2.2 μm): Maximum overlap of actin and myosin → maximum cross-bridges formed → maximum tension
• Too short (<1.65 μm): Actin filaments overlap each other → cross-bridge interference → decreased force
• Too long (>2.2 μm): Insufficient overlap between actin and myosin → fewer cross-bridges → decreased force

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11. Muscle Action Potential vs. Nerve Action Potential

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Summary Flow Chart

Stimulus → Depolarization to threshold (-55 mV)
   ↓
Voltage-gated Na⁺ channels OPEN → Na⁺ influx → Action Potential (+35 mV overshoot)
   ↓
Local currents depolarize adjacent membrane
   ↓
Propagation along nerve (saltatory in myelinated fibers)
   ↓
AP reaches NMJ → ACh release → End-plate potential → Muscle AP
   ↓
Muscle AP propagates along sarcolemma → enters T-tubules
   ↓
DHP receptor → Ryanodine receptor activation → Ca²⁺ released from SR
   ↓
Ca²⁺ binds Troponin C → Tropomyosin shifts → Active sites on actin EXPOSED
   ↓
Myosin heads bind actin → ATP hydrolysis → Power stroke → Actin slides over myosin
   ↓
Sarcomere shortens → MUSCLE CONTRACTS
   ↓
SERCA pumps Ca²⁺ back → Troponin C releases Ca²⁺ → Tropomyosin covers sites
   ↓
Cross-bridges detach → MUSCLE RELAXES

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Nerve Impulse & Muscle Contraction — Simple Explanation

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PART 1: HOW A NERVE IMPULSE TRAVELS

Think of a Nerve Fiber Like a Water Pipe 🔌

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Step 1: Something Triggers the Nerve (Stimulus)

Think of it like a gun trigger — you have to pull hard enough. A light touch does nothing. But once you pull past a certain point — BANG — it fires completely. This is the All-or-Nothing Principle.

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Step 2: The Action Potential Fires 🔥

🔓 Phase 1 — DEPOLARIZATION (Na⁺ rushes IN)

• Sodium (Na⁺) channels suddenly open
• Na⁺ is positive and rushes inside the nerve (like a crowd rushing through an open door)
• The inside flips from -70 mV → +35 mV
• This happens in less than 1 millisecond — incredibly fast!

🔒 Phase 2 — REPOLARIZATION (K⁺ rushes OUT)

• Na⁺ channels close automatically (they self-inactivate)
• Potassium (K⁺) channels open
• K⁺ is also positive and rushes out of the nerve
• Inside goes back from +35 mV → -70 mV (repolarization)

📉 Phase 3 — HYPERPOLARIZATION (brief overshoot)

• K⁺ channels stay open a tiny bit too long
• Inside dips slightly below -70 mV (like a pendulum swinging past center)
• Then everything returns to normal resting state

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Step 3: How Does the Signal TRAVEL? (Propagation)

It's like lighting a fuse — once you light one end, the fire travels all the way to the other end automatically.

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Step 4: Myelinated Nerves Go MUCH Faster (Saltatory Conduction) ⚡

Analogy: Instead of walking every single step, you're jumping from stepping stone to stepping stone across a river — much faster!

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Refractory Period — The "Reset" Time

• Absolute Refractory Period: Cannot fire again no matter what (Na⁺ channels locked shut) — ~1 ms
• Relative Refractory Period: Can fire, but only with a stronger-than-normal stimulus — a few ms

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PART 2: HOW MUSCLES CONTRACT

The Big Picture First 🎯

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Step 1: The Nerve Tells the Muscle to Contract (Neuromuscular Junction)

1. Nerve impulse arrives at the nerve terminal
2. Calcium (Ca²⁺) enters the nerve terminal
3. This triggers the release of a chemical called Acetylcholine (ACh) — like a chemical messenger
4. ACh crosses the gap and lands on receptors on the muscle membrane
5. This opens channels on the muscle → Na⁺ rushes in → muscle gets its own action potential

Think of it as the nerve ringing a doorbell (releasing ACh) → the muscle answers the door (fires its own action potential).

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Step 2: The Signal Goes Deep Inside the Muscle (T-Tubules)

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Step 3: Calcium is Released from Storage (SR → Sarcoplasm)

• It activates special sensors (DHP receptors on T-tubule)
• These sensors pull open calcium release channels (Ryanodine receptors) on the SR
• Calcium floods out into the muscle fiber

Imagine pulling a lever that opens a floodgate — calcium water pours out everywhere around the muscle fibers.

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Step 4: Calcium Unlocks the Muscle (The Key and Lock)

• Actin (thin filaments — like a rail track)
• Myosin (thick filaments — like tiny rowing oars with heads)

• Ca²⁺ binds to Troponin C (a small protein attached to tropomyosin)
• Troponin C changes shape → pulls tropomyosin out of the way
• The binding sites on actin are now exposed — the door is open!
• Myosin heads can now attach to actin

Calcium is literally the key that unlocks the muscle.

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Step 5: The Power Stroke — How Force is Generated 💪

Think of it like a tug-of-war team — hundreds of people (myosin heads) all pulling on the rope (actin) at slightly different times → the rope moves steadily.

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Step 6: The Sliding Filament — What Actually Moves

• Z-disks (the anchors of actin) get pulled closer together
• The whole sarcomere shortens
• Thousands of sarcomeres in series all shorten together → the whole muscle shortens

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Step 7: Muscle Relaxation

1. ACh is broken down by Acetylcholinesterase (enzyme in the NMJ)
2. No more muscle action potentials
3. SERCA pumps actively pump calcium back into the SR (using ATP)
4. Calcium levels fall → Troponin C releases Ca²⁺ → tropomyosin slides back to block actin
5. Myosin heads can no longer attach → cross-bridges stop cycling
6. Muscle relaxes passively (elastic elements return it to resting length)

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THE WHOLE STORY IN ONE SIMPLE CHAIN 🔗

Your brain decides to move
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Nerve impulse travels down motor nerve
(saltatory conduction — jumps between nodes — very fast!)
        ↓
Reaches NMJ → ACh released → crosses gap
        ↓
Muscle fires its own action potential
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Signal dives into T-tubules
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Ca²⁺ released from Sarcoplasmic Reticulum
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Ca²⁺ binds Troponin C → Tropomyosin moves out of way
        ↓
Myosin heads attach to actin
        ↓
Power stroke (ATP energy used) → actin slides over myosin
        ↓
Sarcomeres shorten → MUSCLE CONTRACTS 💪
        ↓
Nerve stops firing → Ca²⁺ pumped back → muscle RELAXES

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Key Points to Remember (Exam Mnemonics)

• Depolarization (Na⁺ in)
• Repolarization (K⁺ out)
• Refractory period (absolute then relative)
• Restoration (Na⁺-K⁺ pump)
• Hyperpolarization (brief overshoot)

• ACh released at NMJ
• Calcium released from SR
• Exposed actin sites (tropomyosin moves)
• Troponin C binds Ca²⁺
• Cross-bridges form
• Power stroke (actin slides)
• SER Ca²⁺ pump → relaxation

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Action Potential Phases - Infographic

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Cross-Bridge Cycle Summary PDF