Cell Physiology and Membrane Potential Chapter Notes | Physiology - NEET PG PDF Download

Introduction to Cells

Definition: Cells are the basic structural and functional units of living organisms, discovered by Robert Hooke in 1665.

Components:

• Cell Membrane: Outer boundary.
• Cytoplasm: Jelly-like material inside the cell.
• Nucleus: Control centre containing genetic material.

Cell Membrane

Structure:

• Thickness: 7.5–10 nanometers.

Composition:

Lipids (40%):

• Phospholipids (25%): Predominantly phosphatidylcholine and sphingomyelin in the outer leaflet; phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol in the inner leaflet.
• Cholesterol (13%): Present in both leaflets, stabilizes membrane at 37°C, maintains permeability and fluidity.
• Other Lipids (4%): Triglycerides = 0%.

Proteins (55%):

• Integral Proteins: Embedded in the membrane via hydrophobic interactions, may span the membrane (e.g., ion channels, transport proteins, receptors, G proteins).
• Peripheral Proteins: Loosely attached via covalent bonds, electrostatic interactions, or hydrogen bonds with integral proteins.
• Carbohydrates (3%): Glycoproteins and glycolipids, externally located, contribute to membrane asymmetry.

Protein-to-Lipid Ratio: Approximately 1:1 in most membranes.

• Highest in inner mitochondrial membrane (3.2), sarcoplasmic reticulum (2.0), outer mitochondrial membrane (1.1).
• Lowest in myelin (0.23), mouse liver cells (0.85), human erythrocyte (1.1).

Membrane Asymmetry:

• Due to unique protein orientations and external carbohydrate location.

Transport Across Membrane:

• Lipid-Soluble Substances: O₂, CO₂, steroid hormones dissolve in the lipid bilayer and cross easily.

• Water-Soluble Substances: Na⁺, Cl⁻, glucose, H₂O cross via water-filled channels, pores, or carriers.

Fluid Mosaic Model

• Proposed: By Singer and Nicolson in 1972.
• Description: Integral proteins are like icebergs in a fluid sea of phospholipids.
• Membrane Fluidity:

Factors Affecting:

• Temperature: Higher temperatures increase fluidity; transition from ordered (gel-like) to disordered (fluid) state at the transition temperature (Tm).

Lipid Composition:

• Unsaturated fatty acyl chains increase fluidity.
• Longer, saturated fatty acids decrease fluidity, increasing Tm.

Cholesterol: Acts as a fluidity buffer.

• Below Tm: Increases fluidity.
• Above Tm: Decreases fluidity.

Membrane Repair:

• Micro-Injury: Rapid resealing via hydrophobic interactions (self-sealing).
• Macro-Injury: Calcium-dependent process.

Lateral Diffusion: Proteins diffuse laterally in the lipid matrix unless restricted, supporting the fluid mosaic model.

Cytoplasm

Composition: Jelly-like, 80% water, contains cytosol (clear liquid with dissolved proteins, electrolytes, glucose) and organelles.

Organelles and Functions​
Nucleus:

• Features: Control center, contains DNA (genes).
• Functions: RNA synthesis, protein synthesis instruction, ribosome subunit formation, cell division control, hereditary information storage.

Ribosomes:

• Features: No limiting membrane, 65% RNA, 35% proteins.
• Functions: Protein synthesis.

Rough Endoplasmic Reticulum (RER):

• Features: Tubular with ribosomes on surface.
• Functions: Protein synthesis, degradation of damaged organelles.

Smooth Endoplasmic Reticulum (SER):

• Features: No ribosomes (agranular).
• Functions: Lipid and steroid synthesis, calcium storage/metabolism, detoxification of toxic substances.

Lysosomes:

• Features: Vesicular, form from Golgi apparatus, acidic interior (pH 5.0 vs. cytoplasm pH 7.2), contain >40 acid hydrolase enzymes.
• Functions: Intracellular digestion, degrade worn-out organelles, remove excess secretory products, bacteria; secrete perforin, granzymes, melanin, serotonin.
• Lysosomal Storage Diseases: Enzyme deficiencies (e.g., Fabry disease: α-galactosidase A deficiency; Gaucher disease: β-galactocerebrosidase deficiency).

Peroxisomes:

• Features: Similar to lysosomes, form by self-replication or budding from SER, contain oxidases (produce H₂O₂) and catalases (break down H₂O₂).
• Functions: Break down fatty acids, detoxify H₂O₂, utilize oxygen, accelerate gluconeogenesis, degrade purine to uric acid, form myelin and bile acids.

Mitochondria:

• Features: Sausage-shaped, outer membrane, inner membrane with cristae, number varies (<100 to several thousand, e.g., high in cardiomyocytes, low in adipocytes).
• Functions: ATP synthesis via oxidative phosphorylation, initiate/regulate apoptosis.

Centrosome:

• Features: Near nucleus, contains two centrioles and pericentriolar material, microtubule-organizing centers (MTOCs) with γ-tubulin.
• Functions: Chromosome movement during cell division, monitors cell division steps.

Cytoskeleton

Components:

Microtubules:

• Structure: Long, hollow, 5-nm walls, 15-nm cavity, made of α- and β-tubulin (13 subunits/ring), γ-tubulin aids formation.
• Features: Polar, assembly at '+' end, disassembly at '−' end, GTP-dependent formation.
• Functions: Intracellular transport, cilia/flagella, centriole-mitotic spindle.
• Inhibitors: Colchicine, vinblastine (prevent assembly); Paclitaxel (Taxol) (stabilizes, prevents organelle movement).

Microfilaments:

• Structure: Solid fibers of actin (15% of cell protein).
• Features: ATP-dependent polymerization/depolymerization, filamentous (F) actin vs. globular (G) actin.
• Functions: Cell junction, muscle contraction, slow axoplasmic transport, critical for contractile apparatus and locomotion.

Intermediate Filaments:

• Structure: Various subunits, connect nuclear to cell membrane.
• Features: Cell-type specific (e.g., vimentin: mesenchyme; cytokeratin: epithelial; glial fibrillary acidic protein: glial cells).
• Functions: Cell adhesion, cell shape.
• Note: Not directly involved in locomotion; absence causes cell rupture, abnormal filaments cause skin blistering.

Intercellular Junctions

Types
Tight Junction (Zonula Occludens):

• Location: Surrounds apical margins of epithelial cells.
• Proteins: Occludin, junctional adhesion molecules (JAMs), claudins.
• Function: Permits paracellular passage of some ions/solutes.

Adherens Junction (Zonula Adherens):

• Location: Basal to tight junction.
• Proteins: Cadherins (Ca²⁺-dependent).
• Function: Attaches microfilaments, signals during organ development/remodeling.

Desmosomes:

• Structure: Thickened membrane areas with intermediate filaments.
• Proteins: Desmoglein.
• Function: Structural support.

Hemidesmosomes:

• Structure: Half-desmosomes, attach to basal lamina.
• Proteins: Integrins.
• Function: Anchors cells to extracellular matrix.

Focal Adhesion:

• Structure: Labile, associated with actin filaments.
• Function: Cell movement, attachment to basal lamina.

Gap Junction:

• Structure: Narrows intercellular space (25 nm to 3 nm), formed by connexons (six connexin subunits).
• Function: Allows passage of ions, sugars, amino acids (MW <1000), electrically/metabolically couples cells.
• Regulation: By cytosolic Ca²⁺, cAMP, H⁺, membrane potential.
• Connexin Mutations: Cause diseases (e.g., Clouston syndrome, inherited deafness, cataracts, Charcot-Marie-Tooth disease).

Transport Across Cell Membrane

General Principles:

• Molecules diffuse across lipid bilayers based on size and oil solubility.

• Small Nonpolar Molecules: O₂, CO₂ diffuse rapidly.

• Small Uncharged Polar Molecules: Water, urea diffuse slowly.

• Charged Molecules/Ions: Highly impermeable due to charge and hydration.

Porins:

• Beta barrel proteins in outer membranes of Gram-negative bacteria, mitochondria, chloroplasts.

• Function: Passive diffusion of medium-sized/charged molecules (sugars, ions, amino acids).

Transport Proteins
Carrier Proteins (Transporters):

• Mechanism: Solute binds, transporter changes shape to move solute across.

Types:

• Facilitated Diffusion: No energy, down concentration gradient.
• Active Transport: Energy-dependent, against gradient.

Characteristics:

• Stereospecificity: e.g., D-glucose transported, not L-glucose.
• Saturation: Transport rate saturates at transport maximum (Tm).
• Competition: Related solutes compete (e.g., galactose inhibits glucose transport).

Channel Proteins:

• Function: Allow rapid ion diffusion (Na⁺, K⁺, Cl⁻, Ca²⁺).
  Features:
  Selectivity: Based on channel diameter, charge, hydration (e.g., K⁺ channels selective for K⁺).
  Gating: Open/closed states.
  Ligand-Gated: Activated by molecule binding.
  Voltage-Gated: Activated by membrane potential changes.
  Mechanically Gated: Activated by membrane stretching.

• Structure: K⁺ channels and aquaporins are tetramers; ligand-gated channels have five subunits; Cl⁻ channels are dimers.

Transport Classification

Passive Transport:

(i) Simple Diffusion:

• No carrier, no Tm, follows Fick’s Law: ( J = -\frac{DA}{X} \Delta C ).
• Example: O₂/CO₂ exchange in alveoli.

(ii) Facilitated Diffusion:

• Carrier-mediated, no energy, saturable (has Tm), follows Michaelis-Menten kinetics.
• Example: Glucose transport via GLUT.

(iii) Non-Ionic Diffusion:

• Weak acids/bases cross in non-ionized form.
• Example: Ammonia transport in GIT/kidney.

Active Transport:
(i) Primary Active Transport:

• Energy from transporter (e.g., Na⁺-K⁺ ATPase).

(ii) Secondary Active Transport:

• Energy indirect (e.g., sodium-linked glucose transport, SGLT).

Transport Characteristics:

• Simple Diffusion: Downhill, no carrier, no energy, unaffected by Na⁺-K⁺ ATPase inhibition.
• Facilitated Diffusion: Downhill, carrier-mediated, no energy, unaffected by Na⁺-K⁺ ATPase inhibition.
• Primary Active Transport: Uphill, carrier-mediated, energy-dependent, inhibited by Na⁺-K⁺ ATPase inhibitors.
• Secondary Active Transport: Uphill (some solutes), carrier-mediated, energy-dependent, inhibited by Na⁺-K⁺ ATPase inhibitors.

Na⁺-K⁺ ATPase Pump

Structure: Heterodimer (α and β subunits).

• α Subunits: α1, α2, α3; intracellular side binds ATP, 3 Na⁺; ECF side binds ouabain, 2 K⁺.

• β Subunits: β1, β2, β3; 3 glycosylation sites on ECF side.

Function:

• Electrogenic pump (3 Na⁺ out, 2 K⁺ in).

• Regulates cell volume, pressure, maintains RMP (5–10%).

Regulation:

• Stimulated by thyroid hormones, insulin, aldosterone, G-actin.

• Inhibited by ouabain.

Osmosis

• Definition: Water flow across a semipermeable membrane from low to high solute concentration.

Osmotic Pressure 

• Modified: (reflection coefficient) accounts for membrane permeability.

  • (σ = 0): Freely permeable (e.g., urea, ineffective osmole).

  • (σ = 1): Impermeable (e.g., sucrose, effective osmole).

Example Calculation:

• RBC in 280 mOsm/kg H₂O (100 fl) moved to 350 mOsm/kg H₂O.
• Formula: ().
• Calculation: .

Oncotic Pressure:

• Osmotic pressure from large molecules (e.g., proteins).
• Normal plasma value: 26–28 mm Hg.
• Does not strictly follow van’t Hoff’s law for large proteins.

Exocytosis

Definition: Delivery of secretory vesicle contents to extracellular fluid.

Mechanism: Vesicle membrane fuses with cell membrane, contents released, Ca²⁺-dependent.

Pathways:

• Nonconstitutive (Regulated): Proteins processed in secretory granules before release.
• Constitutive: Rapid transport to membrane with minimal processing.

Endocytosis

Definition: Uptake of extracellular material into the cell.

Types:

• Phagocytosis: Engulfs large particles (e.g., bacteria).
• Pinocytosis: Uptakes solutions in small vesicles.

Clathrin-Mediated (Receptor-Mediated):

• Occurs at clathrin-coated membrane indentations.
• Clathrin forms triskelion-shaped arrays, surrounds vesicle, then recycles.
• Internalizes receptors/ligands (e.g., nerve growth factor, low-density lipoproteins), important in synaptic function.

Resting Membrane Potential (RMP)

• Definition: RMP is the voltage difference across a cell membrane at rest, where the extracellular surface has an excess of positive charge, and the cytoplasmic surface has an excess of negative charge.

• Typical Value: In neurons, RMP is approximately -70 mV, close to the equilibrium potential of K⁺ ions.
  

Key Equations

• Donnan Effect/Gibbs-Donnan Equilibrium

• Nernst Equation

• Goldman-Hodgkin-Katz (G-H-K) Equation (also known as Goldman constant field equation or chord conductance equation).

Donnan Effect/Gibbs-Donnan Equilibrium

Concept: Occurs due to the presence of a charged, impermeant ion (e.g., negatively charged proteins) on one side of a semipermeable membrane.

• Repulsion and Attraction:

  • Repels similarly charged permeant ions (e.g., Cl⁻) to the opposite side.

  • Attracts oppositely charged permeant ions (e.g., Na⁺) to the same side.

• Result: Asymmetric distribution of permeant ions across the membrane, leading to electroneutrality on each side.

Illustration:

• Setup: A semipermeable membrane separates two solutions (A and B) of NaCl. Solution A contains non-diffusible negatively charged proteins.

• Initial State: Equal Na⁺ concentrations in both solutions.

Equilibrium State:

• Solution A: Higher Na⁺ (held by proteins), lower Cl⁻.

• Solution B: Lower Na⁺, higher Cl⁻.

• Each solution remains electroneutral (total cations = total anions).

Mathematical Expression (Gibbs-Donnan Equation):

• Product of diffusible ion concentrations is equal on both sides: 

• Each side is electrically neutral: 

Osmotic Effect:

• Side with impermeant ions (Side A) has higher osmolarity (e.g., 24 vs. 12 for Side B).

Relative Permeability of Molecules

Order of Permeability:

• Hydrophobic Molecules (e.g., CO₂, O₂, N₂, steroid hormones) ≫ Small Uncharged Polar Molecules (e.g., H₂O, urea, glycerol) ≫ Large Uncharged Polar Molecules (e.g., glucose, sucrose) ≫ Ions (e.g., Na⁺, K⁺, Cl⁻).

Ion Permeability:

• Synthetic Biological Membrane: Cl⁻ ≫ K⁺ ≫ Na⁺.

• Cell Membrane: K⁺ ≫ Cl⁻ ≫ Na⁺.

• Resting Condition Permeability Ratios: K⁺:Cl⁻:Na⁺ = 1.0:0.45:0.04.

Concept of Equilibrium Potential and RMP

Equilibrium Potential: The voltage across a membrane where the chemical and electrical driving forces for an ion are balanced, resulting in no net ion movement.

RMP Generation in Glial Cells:

• Glial cells are permeable only to K⁺ at rest.

• Mechanism:

  • High intracellular K⁺ concentration drives K⁺ efflux (chemical gradient).

  • Efflux leaves behind negative charges (impermeant anions like proteins), creating a positive extracellular surface.

  • At equilibrium, the electrical force (inward) balances the chemical force (outward), establishing the K⁺ equilibrium potential (E_K).

• Result: RMP of glial cells equals E_K (approximately -90 mV).

General Observation:

• Most excitable cells are maximally permeable to K⁺ at rest, so RMP is close to E_K.

• In neurons, RMP (-70 mV) equals the equilibrium potential of Cl⁻.

Nernst Equation

• Purpose: Calculates the equilibrium potential for a specific ion (E_x).

• Formula: 

  • R: Gas constant.

  • T: Temperature (in Kelvin).

  • Z: Valence of the ion (e.g., +1 for Na⁺, -1 for Cl⁻, +2 for Ca²⁺).

  • F: Faraday constant.

  • $[X]_o$, $[X]_i$: Ion concentrations outside and inside the cell.

• Simplified Form (at 37°C): 

  • Conversion factor:  at 37°C.

• Example Calculation:

  • Given: Intracellular [Na⁺] = 15 mM, Extracellular [Na⁺] = 150 mM.

  • 

  • Intuitive Approach: Higher extracellular Na⁺ drives Na⁺ influx, making the inside positive (+60 mV).

• Equilibrium Potentials for Ions:

  • Na⁺: +63 to +65 mV

  • K⁺: -90 to -96 mV

  • Cl⁻: -64 to -70 mV

  • Ca²⁺: +132 to +137 mV

  • H⁺: -12 mV

  • HCO₃⁻: -13 mV

  • Mg²⁺: +9 mV

RMP in Cells with Multiple Permeable Ions

• Unlike Glial Cells: Most mammalian cells (e.g., neurons) are permeable to Na⁺, K⁺, and Cl⁻ at rest.

• Net Ion Flow:

  • At RMP, the sum of ion currents is zero: 

  • RMP settles where there is no net ion movement.

• Dominance of K⁺:

  • Due to high K⁺ permeability, RMP is closest to E_K (-90 mV).

  • Example: Neuron RMP (-70 mV) is influenced by K⁺, Cl⁻, and Na⁺, but dominated by K⁺.

Role of Na⁺-K⁺ ATPase Pump

• Function: Maintains concentration gradients for Na⁺ and K⁺.

  • Pumps 3 Na⁺ out and 2 K⁺ in per ATP hydrolyzed.

• Mechanism:

  • Creates high intracellular K⁺ and low intracellular Na⁺.

  • K⁺ efflux (via leak channels) is balanced by the electrical gradient pulling K⁺ inward.

  • Results in a slight excess of extracellular cations and intracellular anions, establishing RMP.

• Significance: Maintains the conditions necessary for RMP stability.

Recording of RMP

Method:

• Two electrodes connected via an amplifier.

• One electrode inside the cell, one outside.

• Observation: Constant potential difference with the inside negative (e.g., -70 mV in neurons).

Electrode Details:

• Tip diameter < 0.5 micrometers.

RMP and Threshold Voltage of Different Tissues

Calculation of RMP

Goldman-Hodgkin-Katz (G-H-K) Equation

• Purpose: Calculates RMP based on ion concentrations and permeabilities.

• Formula: 

  • P: Permeability of the ion.

  • []_o, []_i: Concentrations outside and inside the cell.

• Dependencies:

  • Distribution of Na⁺, K⁺, and Cl⁻ between extracellular fluid (ECF) and intracellular fluid (ICF).

  • Relative permeabilities of the membrane to these ions.

Changes in RMP

Excitability: Ability of cells (neurons, muscle cells) to produce electrical signals via gated ion channels.

Types of Potentials

Graded Potentials:

• Variable amplitude, conducted decrementally over short distances, no threshold/refractory period.

• Types:

  • Receptor Potential: At afferent neuron endings due to stimuli.

  • Synaptic Potential: In postsynaptic neurons (EPSP: depolarizing, IPSP: hyperpolarizing).

  • Pacemaker Potential: Spontaneous in specialized cells (e.g., SA node).

Action Potentials: Brief, all-or-none, reverse polarity, have threshold/refractory period, conduct without decrement.

Terminology:

• Depolarization: Membrane potential becomes less negative (e.g., -70 mV to -40 mV or +40 mV).

• Repolarization: Returns to RMP after depolarization.

• Hyperpolarization: Becomes more negative (e.g., -70 mV to -90 mV).

• Overshoot: Inside becomes positive (>0 mV).

Effect of Ion Changes:

• Hyperkalemia: Decreases RMP (e.g., -70 mV to -65 mV), due to reduced K⁺ efflux.

• Hypokalemia: Increases RMP.

• Hyponatremia/Hypernatremia: Minimal effect due to low Na⁺ permeability at rest.

Example Question:

• If ECF K⁺ increases from 3.5 to 5 mM, adipose cell RMP becomes less negative (depolarizes) due to reduced K⁺ efflux, not K⁺ influx.