Postgraduate-level comprehensive notes covering cellular physiology, cardiovascular physiology, renal physiology, neurophysiology, and respiratory physiology with integrated systems approach to homeostasis.
Your cell membrane is a phospholipid sandwich with proteins for transport, receptors, and signaling. Stuff moves across it either passively (diffusion, facilitated diffusion) or actively (pumps that burn ATP or use the Na+ gradient). The Na+/K+ ATPase is the most important pump — and a fan-favourite exam topic.
Key exam topics:
Na+/K+ ATPase: 3 Na+ out, 2 K+ in per ATP — electrogenic, consumes 20-40% basal energy
SGLT vs GLUT: secondary active vs facilitated diffusion — do NOT mix them up
SGLT1 is secondary active (uses Na+ gradient, 2 Na+:1 glucose). GLUT2/GLUT4 is facilitated diffusion (just a carrier, no ATP, no Na+). These come up in cross-subject questions with renal physiology.
Membrane Structure
Your cell membrane is about
7.5-10 nm thick phospholipid bilayer
— the famous fluid mosaic model (Singer & Nicolson, 1972). Think of it as a sandwich: hydrophilic phosphate heads face outward (they like water), and hydrophobic fatty acid tails face inward (they hate water). Cholesterol sits between the phospholipids like a thermostat — at high temps it stiffens things up, at low temps it prevents the membrane from turning into a solid block.
Membrane Proteins
About 50% of the membrane is protein. Two types:
Integral proteins
punch through the membrane (transmembrane);
Peripheral proteins
just hitch a ride on the surface. What do they do? Everything: ion channels (selective pores), carriers/transporters (moving stuff), receptors (catching hormones/neurotransmitters), enzymes (like adenylyl cyclase, Na+/K+ ATPase), and cell adhesion molecules (cadherins, integrins, selectins).
Passive Transport
No energy needed — stuff flows downhill (down its gradient).
Three flavours:
Simple diffusion: small, lipid-soluble guys (O₂, CO₂, steroid hormones) slip right through the bilayer. Easy.
Facilitated diffusion: needs a carrier protein (GLUT2 in liver, GLUT4 in muscle/fat — insulin-sensitive) or channel. Saturable and stereospecific.
Fick's law: J = PA(C₁-C₂). Flux = permeability x area x concentration difference. Permeability depends on solubility x diffusivity / membrane thickness.
Active Transport
Needs ATP. We're moving stuff uphill.
Primary active transport: burns ATP directly.
Na+/K+ ATPase (3 Na+ out, 2 K+ in per ATP — sets up the resting membrane potential, consumes 20-40% of your cell's energy!)
Also Ca2+ ATPase (SERCA in SR, PMCA in plasma membrane).
Secondary active transport: uses the Na+ gradient (which was set up by the Na+/K+ ATPase) to drag other stuff along.
SGLT1 (2 Na+ per glucose, in intestine), NCX (3 Na+ in, 1 Ca2+ out — cardiac muscle), NHE (1 Na+ in, 1 H+ out — renal tubule).
Vesicular transport: endocytosis (phagocytosis = cell eating, pinocytosis = cell drinking, receptor-mediated via clathrin-coated pits) and exocytosis (regulated or constitutive).
Do NOT confuse SGLT1 (secondary active, Na+/glucose symport, 2 Na+:1 glucose) with GLUT2 (facilitated diffusion, liver/pancreas) or GLUT4 (facilitated diffusion, insulin-dependent in muscle/fat). Also: Na+/K+ ATPase pumps 3 Na+ OUT, 2 K+ IN per ATP hydrolysis. Digitalis/ouabain inhibits this pump -> increased intracellular Na+ -> decreased NCX -> increased intracellular Ca2+ -> positive inotropy.
NEET PG 2019: Ouabain inhibits Na+/K+ ATPase. Explain the positive inotropic effect. A: Ouabain -> decreased Na+/K+ ATPase -> increased intracellular Na+ -> decreased NCX activity (3Na+ in:1Ca2+ out) -> increased intracellular Ca2+ -> increased Ca2+ available for SR uptake and release -> increased contractility. This is the mechanism of digitalis glycosides (digoxin) in heart failure. Also: digitalis increases vagal tone (parasympathomimetic effect) -> decreased HR + slowed AV conduction -> useful in AF with RVR.
Fluid mosaic model with transport mechanisms across the cell membrane
Membrane Potential and Action Potential Generation
Resting Membrane Potential (RMP)
The resting membrane potential (RMP) of a typical mammalian neuron is approximately -70 mV (inside negative relative to outside).
This potential is established by:
The concentration gradients of K+ (intracellular 140 mM, extracellular 4 mM — strongly driven to leave the cell), Na+ (intracellular 12 mM, extracellular 145 mM — strongly driven to enter), and Cl-
The selective permeability of the membrane (at rest, the membrane is 50-100 times more permeable to K+ than to Na+ due to open K+ leak channels — K2P channels, specifically TWIK and TREK)
The electrogenic Na+/K+ ATPase (contributes -4 to -10 mV directly by pumping 3 Na+ out and 2 K+ in)
The Nernst equation calculates the equilibrium potential for a single ion: Eion = (RT/zF) × ln([ion]out/[ion]in). At 37°C: EK ≈ -94 mV, ENa ≈ +61 mV, ECl ≈ -73 mV, ECa ≈ +123 mV.
The Action Potential
The action potential is a rapid, all-or-none depolarization of the membrane that propagates along excitable cells (neurons, muscle fibers).
It is generated by the coordinated opening and closing of voltage-gated sodium and potassium channels. The phases of the action potential in a neuron:
Resting state (-70 mV, all voltage-gated channels closed)
Threshold (typically -55 mV, when the depolarization is sufficient to open voltage-gated Na+ channels — the point of no return)
Depolarization (rapid Na+ influx through NaV channels, membrane potential swings toward ENa, reaching approximately +30 mV)
Repolarization (NaV channels inactivate — the h-gate closes, and voltage-gated Kv channels open, K+ efflux drives the membrane back toward EK)
Return to RMP (Kv channels close, leak channels restore the resting state)
Action Potential Propagation
Action potentials propagate along axons without decrement, maintaining constant amplitude.
In unmyelinated axons, propagation occurs by local current spread (continuous conduction, velocity 0.5-10 m/s). In myelinated axons, action potentials are regenerated only at the nodes of Ranvier (saltatory conduction, velocity 5-120 m/s), because myelin acts as an insulator with high resistance and low capacitance.
Saltatory conduction is faster, more energy-efficient (less Na+/K+ ATPase activity required), and allows smaller diameter axons to conduct more rapidly.
The conduction velocity is proportional to the axon diameter (approximately 6 m/s per μm of fiber diameter in myelinated axons). The safety factor for propagation (the ratio of action potential current available to threshold current required) is normally >5, ensuring reliable transmission.
Fiber types: Aα (motor, proprioception, 15-120 m/s, largest, myelinated). Aβ (touch, pressure, 5-30 m/s). Aδ (fast pain, cold, 5-30 m/s, thin myelinated). B (preganglionic autonomic, 3-15 m/s, thin myelinated). C (slow pain, warm, postganglionic autonomic, 0.5-2 m/s, unmyelinated, smallest). Mnemonic: "A Alpha is Biggest and Fastest, C is Slowest and Smallest."
Voltage-Gated Sodium Channels and Refractory Periods
The voltage-gated sodium channel (NaV) has three states: closed (activated at rest, activatable), open (activated by depolarization, the m-gate opens, conducting Na+ — about 0.5-1 ms), and inactivated (the h-gate closes after 0.5-1 ms, preventing further Na+ influx until the membrane repolarizes).
This inactivation is responsible for the absolute refractory period (1-2 ms, during which no stimulus can generate another action potential). The relative refractory period follows (3-5 ms, during which a stronger-than-normal stimulus can generate an action potential due to continued K+ efflux and gradual recovery from inactivation).
Important clinical correlations of the action potential: (1) Local anesthetics (lidocaine, bupivacaine) block voltage-gated Na+ channels, preventing action potential generation in sensory neurons — they work more effectively on small, myelinated fibers (Aδ and C fibers) mediating pain. (2) Tetrodotoxin (TTX, from pufferfish) and saxitoxin (from shellfish) block NaV channels, causing paralysis and respiratory failure. (3) Mutations in NaV1.4 (skeletal muscle) cause paramyotonia congenita and hyperkalemic periodic paralysis. (4) Class I antiarrhythmics (quinidine, flecainide) block cardiac NaV1.5 channels.
The absolute refractory period ensures unidirectional propagation and limits the firing frequency (maximum ~300-1000 Hz in neurons, up to 1 kHz in auditory neurons).
The strength-duration relationship: threshold stimulus strength is inversely related to duration.
Chronaxie is the minimum duration required to excite the tissue using a current twice the rheobase intensity (rheobase = minimum current amplitude for an infinitely long stimulus).
Ion Channel Classification and Patch Clamp Technique
Ion channels are pore-forming membrane proteins that allow specific ions to pass down their electrochemical gradients. They are classified by gating mechanism:
Voltage-gated channels
— open/close in response to changes in membrane potential (NaV, CaV, Kv, HCN). Each has a voltage-sensing domain (S4 segment with positively charged residues).
Ligand-gated channels
— open/close in response to binding of a chemical ligand (nicotinic AChR, GABA-A, AMPA, NMDA, glycine, P2X).
Mechanosensitive channels
— respond to mechanical stretch (PIEZO1, PIEZO2 in touch and proprioception; TRPV4, TREK-1).
Second messenger-gated channels
— respond to intracellular signals (cAMP-gated CNG channels in olfactory and photoreceptor cells, IP3 receptors, ryanodine receptors).
The patch clamp technique (Neher and Sakmann, Nobel Prize 1991) allows recording of current through a single ion channel. Configurations: cell-attached (seal on intact cell), whole-cell (ruptured patch recording from entire cell), inside-out (excised patch with cytoplasmic side exposed), outside-out (excised patch with extracellular side exposed).
Q: The Nernst equation predicts an equilibrium potential of approximately +61 mV for sodium at 37°C. If the extracellular sodium concentration is 145 mM and intracellular is 12 mM, what would happen to the resting membrane potential if the extracellular sodium concentration suddenly increased to 200 mM? A: E_Na = 61.5 × log([Na+]_out/[Na+]_in) = 61.5 × log(200/12) ≈ +73 mV. However, the resting membrane potential is primarily determined by K+ conductance (the membrane is 50-100 times more permeable to K+ than Na+ at rest), so the actual RMP would change minimally (~1-2 mV depolarization).
1. RMP = -70mV (neuron). Determined primarily by K+ leak (E_K = -94mV). Na+/K+ ATPase contributes -4 to -10mV (electrogenic).
2. Nernst: Eion = 61.5 x log([ion]out/[ion]in) at 37C. GHK equation accounts for multiple ions and permeabilities (P_K:P_Na:P_Cl = 1:0.02:0.1 at rest).
3. Threshold = -55mV. All-or-none. NaV activates (m-gate opens), then inactivates (h-gate closes after 0.5-1ms).
4. Absolute refractory period: NaV inactivated, no AP possible (1-2ms). Relative: K+ conductance elevated (3-5ms), stronger stimulus needed.
5. Saltatory conduction: 5-120 m/s at nodes of Ranvier (energy-efficient, smaller axons possible). Continuous: 0.5-10 m/s unmyelinated.
6. Fiber types: Aalpha (motor/proprioception, 15-120 m/s, largest, myelinated). Abeta (touch, 30-70 m/s). Adelta (fast pain, 5-30 m/s). B (preganglionic autonomic). C (slow pain, 0.5-2 m/s, unmyelinated).
7. Local anesthetics: use-dependent NaV block (bind open/inactivated state); less effective in acidic tissue (infection).
8. Patch clamp (Neher & Sakmann, Nobel 1991): cell-attached --> whole-cell --> inside-out --> outside-out configurations.
ION DISTRIBUTION: 'Salty Banana' - Na+ (Salt) outside (145mM), K+ (Banana) inside (140mM). Nernst at 37C: E_ion = 61.5 x log(out/in). E_K = -94mV, E_Na = +61mV. GHK: includes relative permeabilities. At rest, membrane is 50-100x more permeable to K+ than Na+, so RMP is close to E_K.
Local anesthetics (lidocaine, bupivacaine): bind to the open/inactivated state of NaV channels from the INTRACELLULAR side (must cross membrane in uncharged form, then become charged intracellularly - pH-dependent). Use-dependent block: rapidly firing pain fibers (Adelta, C) are blocked before motor fibers (Aalpha). Acidic tissue (infection, inflammation) traps LA in ionized form extracellularly --> decreased efficacy. Adding epinephrine causes vasoconstriction --> decreased systemic absorption --> prolonged duration + decreased toxicity. Bupivacaine is more cardiotoxic than lidocaine (stronger NaV binding, slower dissociation).
Transmembrane ion distribution establishing the resting membrane potential
Sequential phases of the action potential with ion channel states
Voltage-gated, ligand-gated, and mechanosensitive ion channel types
Skeletal Muscle Physiology and Neuromuscular Junction
Skeletal Muscle Ultrastructure
Skeletal muscle is composed of multinucleated muscle fibres (myofibres), each containing hundreds of myofibrils arranged in parallel. Each myofibril is organized into sarcomeres — the basic contractile unit — bounded by Z-discs (Z-lines).
The sarcomere contains thick filaments (myosin, in the A band) and thin filaments (actin, tropomyosin, troponin complex, extending from the Z-disc into the A band). The I band (isotropic) is the region of thin filaments only; the H zone is the region of thick filaments only, without thin filament overlap. During contraction the I band and H zone shorten while the A band length remains constant — this is the sliding filament theory.
Crossbridge Cycle
The crossbridge cycle: myosin head binds to actin when Ca2+ concentration rises → power stroke (myosin head pivots, pulling thin filament toward the M line, requiring 1 ATP per crossbridge cycle) → ATP binds myosin, detaching the head → ATP hydrolysis re-cocks the myosin head → cycle repeats as long as Ca2+ is present.
Rigor mortis is the stiffening of muscles after death, caused by ATP depletion preventing myosin head detachment from actin.
Troponin-Tropomyosin Regulation
At rest, tropomyosin physically blocks the myosin-binding sites on actin. The troponin complex (TnI — inhibitory, TnT — tropomyosin-binding, TnC — Ca2+-binding) anchors tropomyosin. When intracellular Ca2+ rises from ~100 nM to ~1 μM, Ca2+ binds TnC, causing a conformational change that moves tropomyosin away from the myosin-binding site, enabling crossbridge formation.
Cardiac troponins (cTnI and cTnT) are the gold-standard biomarkers for myocardial infarction — they are structurally distinct from skeletal muscle isoforms, providing cardiac specificity.
Muscle Fibre Types and Fatigue
Skeletal muscle fibres are classified as type I (slow-twitch, oxidative, fatigue-resistant, small diameter, red, rich in mitochondria and myoglobin — suited for endurance exercise), type IIa (fast-twitch oxidative-glycolytic, intermediate fatigue resistance), and type IIx/IIb (fast-twitch glycolytic, largest diameter, fatigues rapidly, generates peak force — suited for sprinting).
The size principle of motor unit recruitment (Henneman): motor units are recruited in order of increasing size from slow (type I) to fast (type IIa, IIx). Smaller motor neurons have lower thresholds for activation and are recruited first. Maximum force requires activation of large, high-threshold fast-twitch motor units.
Summation and Tetanus
A single action potential produces a single twitch (a brief contraction-relaxation cycle). When action potentials arrive before the muscle fully relaxes, the contractions summate (temporal summation). At high stimulation frequencies (>50 Hz for fast fibres), a sustained maximal contraction (tetanus) occurs because Ca2+ accumulates in the sarcoplasm, maximally activating troponin C. The ratio of tetanic to twitch force is approximately 4–5:1.
Key muscle physiology points: A-band constant; I-band and H-zone shorten; rigor mortis = ATP depletion; type I = slow/fatigue-resistant; size principle recruits slow motor units first; troponin C binds Ca2+.
1. Sliding filament: I-band + H-zone shorten during contraction. A-band constant. Sarcomere = Z-disc to Z-disc (~2.2um resting).
2. Crossbridge cycle: 1 ATP per cycle. Myosin binds actin (Ca2+ present) --> power stroke --> ATP binds --> detaches --> ATP hydrolysis re-cocks. Rigor mortis = no ATP.
3. Troponin: TnC (Ca2+ binding, 4 sites), TnI (inhibitory, masks myosin site), TnT (tropomyosin-binding). Ca2+ rises 100nM --> 1uM.
4. Fiber types: Type I (slow oxidative, red, high mitochondria/myoglobin, endurance/marathon). Type IIa (fast ox-glycolytic, intermediate). Type IIx/IIb (fast glycolytic, white, sprint/weightlifting).
5. Henneman size principle: small slow --> large fast motor units. Smaller motor neurons have lower activation threshold.
6. Summation --> tetanus at >50Hz. Tetanic:twitch force ratio ~4-5:1. Ca2+ accumulates with high-frequency stimulation.
7. Excitation-Contraction coupling: AP in T-tubule --> CaV1.1 (DHP receptor, voltage sensor) conformational change --> mechanical coupling --> RyR1 opens --> Ca2+ released from SR.
8. Duchenne MD: dystrophin mutation (Xp21), sarcolemma fragility, CK >10,000, Gower sign, calf pseudohypertrophy, dilated cardiomyopathy.
Sarcomere bands: I = Isotropic (thin filaments only, light). A = Anisotropic (thick filaments, dark). H = Helle (German for 'bright', thick only, no thin overlap). M = Mittel (middle line). Z = Zwischenscheibe (between discs)." During contraction: I-band shortens, H-zone shortens, A-band constant. "I HATE contraction" - I and H shorten.
Muscle disorders: Duchenne MD - X-linked recessive, dystrophin mutation (Xp21), onset 2-5 years, Gower's sign, wheelchair by age 12, death by 20-30 (respiratory/cardiac failure). Becker MD - partially functional dystrophin, milder, later onset. Myasthenia gravis - anti-nAChR antibodies, fluctuating weakness, ptosis/diplopia, decrement on RNS. LEMS - anti-CaV2.1, proximal weakness, increment after exercise, associated SCLC. Malignant hyperthermia - RyR1 mutation, succinylcholine/halothane trigger, dantrolene treatment.
Ultrastructure of the sarcomere with actin-myosin crossbridge cycle and troponin regulation
Smooth Muscle Physiology and Vascular Tone
Smooth Muscle Structure and Contraction
Smooth muscle lacks the sarcomeric organisation of striated muscle and does not have troponin. It is found in the walls of hollow visceral organs (blood vessels, GI tract, bronchi, uterus, bladder) and is involuntarily controlled by the autonomic nervous system, hormones, and local factors.
Smooth muscle contains thick (myosin) and thin (actin) filaments, but they are arranged obliquely, attached to dense bodies (equivalent of Z-discs) and the cell membrane. Caldesmon and calponin are thin filament-associated regulatory proteins. Contraction is initiated by an increase in intracellular Ca2+ (from extracellular influx through L-type Ca2+ channels and IP3-mediated release from the sarcoplasmic reticulum).
The latch state: smooth muscle can maintain prolonged contraction with minimal ATP consumption (the "latch bridge" phenomenon) — dephosphorylated attached crossbridges remain attached slowly cycling. This is important in sustained vascular tone and sphincter function.
Rho-kinase (ROCK) pathway — central regulator of vascular tone: Ang II, ET-1, thromboxane A2 → RhoA activation → ROCK activation → ROCK phosphorylates and inhibits MLCP (myosin light chain phosphatase) → increased MLC phosphorylation at the same [Ca2+] → Ca2+ sensitisation (increased smooth muscle contraction without increase in cytosolic Ca2+). Rho-kinase inhibitors (fasudil) are used in pulmonary arterial hypertension and cerebral vasospasm.
Endothelium-Derived Vasoactive Mediators
Nitric oxide (NO): synthesised from L-arginine by endothelial NO synthase (eNOS, NOS3) in response to shear stress, ACh (via M3 on endothelium), bradykinin, and substance P. NO diffuses into VSMCs → activates soluble guanylyl cyclase (sGC) → ↑cGMP → cGMP-dependent protein kinase (PKG) → MLCP activation and Ca2+ channel inhibition → vasodilation. Phosphodiesterase type 5 (PDE5) degrades cGMP — inhibited by sildenafil, tadalafil (erectile dysfunction, PAH).
Prostacyclin (PGI2): synthesised by endothelial COX-1 from arachidonic acid → binds IP receptor → ↑cAMP → PKA → MLCK inhibition and MLCP activation → vasodilation and platelet aggregation inhibition.
Endothelin-1 (ET-1): the most potent endogenous vasoconstrictor; synthesised by endothelium; acts on ETA receptors on VSMCs (Gq → vasoconstriction) and ETB receptors on endothelium (Gq → NO and PGI2 release, Gi → vasoconstriction on VSMCs). ET-1 excess is implicated in pulmonary arterial hypertension — dual endothelin receptor antagonists (bosentan, macitentan) reduce pulmonary vascular resistance.
Myogenic Autoregulation
Myogenic autoregulation (the Bayliss effect): increased intraluminal pressure stretches vascular smooth muscle → activation of mechanosensitive cation channels (TRPC6, Piezo1) → membrane depolarisation → Ca2+ influx through voltage-gated L-type Ca2+ channels → MLCK activation → vasoconstriction, restoring diameter and maintaining constant flow despite pressure changes. This is the primary autoregulatory mechanism in the kidney, brain, and gut.
Calmodulin-MLCK pathway and endothelial regulation of vascular smooth muscle tone
Cell Signaling and Signal Transduction
Cell-Cell Junctions
Cell junctions connect cells to each other and to the extracellular matrix, providing mechanical strength and enabling intercellular communication.
Tight junctions (zonula occludens) seal the paracellular space and maintain polarity (claudins, occludins). Adherens junctions (zonula adherens) provide attachment via cadherins linked to actin via catenins. Desmosomes provide strong adhesion via desmogleins linked to intermediate filaments. Gap junctions (connexons) allow passage of ions and small molecules, enabling electrical coupling.
Hemidesmosomes anchor epithelial cells to basement membrane via integrins.
Cell signaling is the process by which cells communicate with each other to coordinate physiological functions.
Signaling molecules (ligands) include neurotransmitters, hormones, growth factors, cytokines, and paracrine/autocrine factors. Signaling modes:
endocrine (hormones transported via blood, long distance), paracrine (local diffusion to neighboring cells — e.g., histamine, nitric oxide), autocrine (signaling acts on the same cell that secreted it — e.g., IL-2 in T cell activation, growth factors in wound healing), synaptic (neurotransmitters across the synaptic cleft, fast and precise), and juxtacrine (direct cell-cell contact through membrane-bound molecules — e.g., Notch-Delta signaling in development).
Major Receptor Classes
Ion channel-coupled receptors (ionotropic receptors): ligand-gated ion channels that open upon ligand binding, mediating fast synaptic transmission (nicotinic ACh receptor — cation channel, depolarizing; GABA-A receptor — Cl- channel, hyperpolarizing/inhibitory; NMDA and AMPA glutamate receptors — cation channels, excitatory).
cAMP (synthesized by adenylyl cyclase, degraded by phosphodiesterase, activates PKA which phosphorylates many target proteins including CREB transcription factor)
IP3 (releases Ca2+ from endoplasmic reticulum via IP3 receptors)
DAG (activates PKC)
Ca2+ (intracellular concentration usually 100 nM, rises to 500-1000 nM upon stimulation, binds calmodulin → CaM-Kinases, troponin C in muscle, synaptotagmin in neurotransmitter release)
Case: A 45-year-old woman presents with episodic severe hypertension, palpitations, and diaphoresis. Pheochromocytoma (adrenal medullary tumor) is diagnosed. The pathophysiology involves excessive catecholamine secretion acting on GPCRs: β1 receptors (positive chronotropy and inotropy), α1 receptors (vasoconstriction, increased BP), and β2 receptors (bronchodilation, skeletal muscle vasodilation). The combination of α-mediated vasoconstriction with β-mediated cardiac stimulation explains the clinical presentation. Diagnosis is confirmed by elevated plasma metanephrines or 24-hour urinary catecholamines.
