---

PHYSIOLOGY MASTER NOTES

---

PART 1: MEMBRANE TRANSPORT MODES

A. Types of Transport (Overview)

---

B. Na⁺-K⁺ ATPase Pump (Primary Active Transport)

1. 3 Na⁺ bind to intracellular sites on the pump
2. ATP is hydrolyzed → pump becomes phosphorylated (conformational change)
3. 3 Na⁺ are expelled to the extracellular space
4. 2 K⁺ bind from extracellular side
5. Dephosphorylation → pump returns to original conformation
6. 2 K⁺ enter the cell

• Net result: 3 Na⁺ out, 2 K⁺ in per cycle - electrogenic (generates a net outward positive current)

• Maintains resting membrane potential (cell interior negative)
• Prevents cell swelling (by controlling intracellular osmolality)
• Powers secondary active transport (provides Na gradient used by SGLT, NHE, etc.)
• Maintains excitability of nerve and muscle cells

---

C. Facilitated Diffusion

• Movement down the electrochemical gradient using a carrier protein or channel - no energy required
• Shows saturation kinetics (Vmax) and specificity
• Examples:
  • GLUT-1 to GLUT-5 - glucose entry into cells (GLUT-4 is insulin-dependent in muscle/fat)
  • Aquaporins (AQP) - water channels
  • Ion channels (Na⁺, K⁺, Ca²⁺, Cl⁻ channels)

• Carrier-mediated (shows saturation, competitive inhibition)
• Faster rates at low concentrations
• Can be regulated (e.g., GLUT-4 insertion stimulated by insulin)

---

D. Edema - Pathophysiology

Net filtration = Kf [ (Pc - Pi) - σ(πc - πi) ]

---

PART 2: HOMEOSTASIS

1. Receptor/sensor - detects deviation from set point
2. Control center (integrating center) - processes and compares to set point
3. Effector - corrects the deviation

• Negative feedback - most common; opposes the change (e.g., thermoregulation, blood pressure, blood glucose)
• Positive feedback - amplifies the change (e.g., childbirth oxytocin surge, LH surge at ovulation, blood clotting cascade)

• Core body temp: 37°C
• Blood pH: 7.35-7.45
• Plasma osmolality: 280-295 mOsm/kg
• Blood glucose: 70-100 mg/dL (fasting)

---

PART 3: NERVE & MUSCLE PHYSIOLOGY

A. Action Potential

• Maintained by: K⁺ leakage outward, Na-K ATPase pump

---

B. All-or-None Law

"Once threshold is reached, the action potential fires with maximum amplitude regardless of the strength of the stimulus. Subthreshold stimuli produce no response."

• The size and duration of an action potential are constant for a given neuron
• Stimulus strength is coded not by AP amplitude but by frequency of firing
• The law applies to: nerve fibers, skeletal muscle fibers, cardiac muscle

---

C. Refractory Period

• No stimulus, however strong, can produce another AP
• Na⁺ activation gates are open OR Na⁺ inactivation gates are closed (h gates shut)
• Duration: ~1-2 ms in nerve; 200-300 ms in cardiac muscle (protective - prevents tetanus)

• Follows ARP; a stronger-than-normal stimulus CAN fire another AP
• K⁺ channels still open; membrane hyperpolarized
• Corresponds to repolarization/after-hyperpolarization phase

---

D. Saltatory Conduction

• Action potential can only occur at the nodes (where ion channels are concentrated)
• Current flows from one depolarized node to the next resting node through extracellular fluid
• The AP "jumps" from node to node (saltus = jump)

1. Speed - conduction velocity up to 100-120 m/s (vs. 0.5-2 m/s in unmyelinated fibers)
2. Energy efficiency - ion exchange only at nodes, less Na-K pump activity needed
3. Protection - if one node is blocked, current can jump 2-3 nodes

---

E. Wallerian Degeneration

• Hours: Disruption of axonal plasma membrane → rapid influx of Ca²⁺ and Na⁺
• This activates proteolytic enzymes (calpains) - cascade resembling apoptosis
• Day 3: Schwann cells retract from nodes of Ranvier
• Days 3-7: Schwann cells and macrophages digest myelin (phagocytosis)
• The entire axonal process takes ~1 week
• Schwann cells proliferate and form Bands of Büngner (guides for regeneration)

• Nucleus moves eccentrically
• Nissl substance (rough ER) dissolves/disperses
• Cell body swells
• Upregulation of transcription factors: switches from maintenance mode to protein synthesis mode
• Key protein upregulated: c-Jun (in Schwann cells)

• Axon sprouts grow from proximal stump at ~1-4 mm/day
• Collateral sprouting from intact axons reinnervates denervated muscle
• Remyelination occurs with thinner myelin and shorter internodes

---

F. Strength-Duration Curve

• Rheobase: The minimum stimulus strength (intensity/current) that can trigger an AP when applied for an infinite (very long) duration
• Chronaxie: The minimum duration of a stimulus needed to fire an AP when applied at twice the rheobase intensity
  • Chronaxie is a measure of tissue excitability
  • Short chronaxie = more excitable (e.g., motor nerve: ~0.05 ms)
  • Long chronaxie = less excitable (e.g., cardiac muscle: ~2 ms)

• Distinguish nerve vs. muscle excitability (denervated muscle has longer chronaxie)
• Assess nerve injuries (Wallerian degeneration raises chronaxie)
• Design electrical stimulation parameters in physiotherapy

---

PART 4: NEUROMUSCULAR JUNCTION (NMJ) TRANSMISSION ⭐ IMPORTANT

Anatomy of the Motor End Plate

• Presynaptic terminal: axon terminal filled with ~300,000 ACh vesicles + mitochondria
• Synaptic cleft: 20-30 nm wide, contains acetylcholinesterase (AChE)
• Postsynaptic membrane: muscle membrane with deep subneural clefts (increase surface area) and nicotinic ACh receptors (nAChR) concentrated at the mouths of clefts

Step-by-Step Transmission

• AP travels down the motor neuron to the presynaptic terminal

• Depolarization opens voltage-gated P-type (and L-type) Ca²⁺ channels at active zones
• Ca²⁺ flows from extracellular fluid into the nerve terminal
• No Ca²⁺ = no ACh release (critical concept)
• Doubling [Ca²⁺] increases quantal ACh release 16-fold

• Ca²⁺ activates Ca²⁺-calmodulin-dependent protein kinase
• This phosphorylates synapsin proteins that anchor vesicles to the cytoskeleton
• Vesicles are freed → move to active zones → dock → fuse with membrane (exocytosis)
• ~125 vesicles released per AP (each vesicle = 1 quantum = ~10,000 ACh molecules)

• Nicotinic ACh receptors are ligand-gated ion channels (pentameric: 2α, 1β, 1γ, 1δ)
• ACh binds 2 alpha subunits → channel opens
• Na⁺ flows in >> K⁺ flows out → End-plate potential (EPP) generated

• EPP is large enough (always suprathreshold) to depolarize adjacent voltage-gated Na⁺ channels
• Full muscle AP fires (All-or-None)

• Acetylcholinesterase in the cleft hydrolyzes ACh → acetate + choline
• Choline is taken back up by presynaptic terminal (reused for ACh synthesis)
• This terminates the signal within milliseconds

---

Applied: Myasthenia Gravis (MG) ⭐

• Autoantibodies (IgG) directed against nicotinic ACh receptors (nAChR) on the postsynaptic muscle membrane
• Antibodies against the Main Immunogenic Region (MIR) of the α subunit
• Mechanism of receptor loss: complement activation + accelerated internalization and destruction of receptors
• Result: Reduced surface density of nAChR → reduced EPP amplitude → failure of NMJ transmission

• Fatigable muscle weakness - worse with repeated use, better after rest
• Ptosis, diplopia (extraocular muscles most commonly affected first)
• Dysphagia, dysarthria, dyspnea
• Bimodal age: women in 20s (thymic hyperplasia) | men in 60s (thymoma)
• Crisis = respiratory muscle weakness → respiratory failure

1. Ocular MG - only extraocular muscles
2. Generalized MG - all skeletal muscles

• Anti-AChR antibodies (positive in ~85%)
• Anti-MuSK antibodies (seronegative MG)
• Tensilon (edrophonium) test - short-acting AChE inhibitor → transient improvement
• Repetitive nerve stimulation: decremental response (amplitude decreases with repeated stimulation)
• Single-fiber EMG: increased jitter

• Antibodies against presynaptic voltage-gated Ca²⁺ channels (not AChR)
• Less ACh released
• Weakness improves with repeated use (more Ca²⁺ accumulates)
• Associated with small cell lung cancer
• Incremental response on repetitive nerve stimulation

---

PART 5: EXCITATION-CONTRACTION COUPLING (ECC) ⭐ IMPORTANT

Molecular Basis of Muscle Contraction (Sliding Filament Theory)

• Thick filament: Myosin (tail + globular head with actin-binding site + ATPase activity)
• Thin filament: Actin + Tropomyosin + Troponin complex
  • Troponin C (TnC) - binds Ca²⁺
  • Troponin I (TnI) - inhibitory subunit
  • Troponin T (TnT) - binds tropomyosin
• At rest: tropomyosin blocks the myosin-binding sites on actin

The Transverse Tubule (T-Tubule) - Sarcoplasmic Reticulum (SR) System

• T-tubules = invaginations of sarcolemma running transversely → carry AP to cell interior
• In skeletal muscle: T-tubule at A-I junction (2 per sarcomere)
• SR surrounds myofibrils; terminal cisternae abut T-tubules
• Triad = 1 T-tubule flanked by 2 terminal cisternae of SR

Steps of ECC in Skeletal Muscle

• Ca²⁺ concentration rises from <10⁻⁷ M (resting) to 2×10⁻⁴ M (500-fold increase)
• This is 10× the level needed for maximum contraction

1. Ca²⁺ binds Troponin C
2. Conformational change in troponin complex → tropomyosin shifts → exposes myosin-binding sites on actin
3. Myosin head (with ADP + Pi) attaches to actin → forms cross-bridge
4. Power stroke - myosin head pivots → thin filament pulled toward M line (ADP + Pi released)
5. New ATP binds → cross-bridge detaches
6. ATP hydrolysis re-cocks the myosin head (high-energy configuration)
7. Cycle repeats as long as Ca²⁺ is present

In rigor mortis (after death): no ATP → myosin remains attached to actin permanently

• After AP ends, SERCA (Sarcoplasmic Reticulum Ca²⁺-ATPase) pump actively pumps Ca²⁺ back into SR
• SR concentrates Ca²⁺ ~10,000-fold using ATP
• Calsequestrin inside SR binds up to 40 Ca²⁺ per molecule (storage protein)
• Ca²⁺ concentration in cytosol falls back below threshold → tropomyosin re-blocks actin sites → relaxation

Key Difference: Skeletal vs. Cardiac ECC

---

QUICK PHARMACOLOGY LINKS

---