Cell Membrane and Membrane Transport

Structural Components of the Cell Membrane

• Phospholipid Architecture:

  • Hydrophilic Head: The water-attracting portion of the phospholipid, composed of a Phosphate group and a Glycerol backbone ($R-O-$ attached to $OP-O$ and $CH_2-CH-CH_2$).

  • Hydrophobic Tails: Water-repelling portions composed of fatty acids.

  • Saturated Fatty Acid: Straight-chain fatty acid tails without double bonds.

  • Unsaturated Fatty Acid: Kinked fatty acid tails containing one or more double bonds.

• Membrane Organizations:

  • Lipid-bilayer Sheet: A double layer of phospholipids with tails facing inward.

  • Lipid-bilayer Sphere: A spherical structure formed by a phospholipid bilayer.

  • Single-layer Lipid Sphere: A micelle-like structure with a single layer of lipids.

• Associated Membrane Proteins and Carbohydrates:

  • Integral Membrane Protein: Proteins that span or are deeply embedded within the phospholipid bilayer.

  • Peripheral Membrane Protein: Proteins located on the surface of the membrane.

  • Glycoprotein: A protein molecule with a carbohydrate attached.

  • Glycolipid: A lipid molecule with a carbohydrate attached.

  • Protein Channel: A pore-forming protein that allows for the passage of specific molecules.

  • Cholesterol: Steroid molecules interspersed within the hydrophobic tail region to modulate fluidity.

  • Cytoskeletal Filaments: Internal structures that support the cell membrane from the cytoplasmic space.

Fundamental Principles of Membrane Transport

• Permeability of the Phospholipid Bilayer:

  • Lipid-soluble molecules: Steroids, $O_2$, and $CO_2$ can pass directly through the bilayer.

  • Small polar molecules: Water, urea, ethanol, and glycerol are able to pass through the bilayer despite their polarity due to their small size.

  • Ions and large polar molecules: The passage of these substances requires integral membrane proteins acting as transport proteins.

• General Terminology:

  • Transport Proteins: Often referred to as transporters or, less commonly, carriers.

  • Classification: Transport systems are categorized as either passive or active transporters. The majority of biologically relevant molecules and ions utilize these proteins to cross the membrane.

Passive Transport Mechanisms

• Definition: Passive transport does not require direct energy expenditure. Instead, it utilizes existing concentration gradients, with movement always occurring down an electrochemical gradient.

• Types of Passive Transport:

  • Simple Diffusion: Movement of molecules directly through the lipid bilayer.

  • Passive Diffusion (Channel-mediated): Movement facilitated by a channel protein.

  • Facilitated Diffusion (Carrier-mediated or Uniport): Movement mediated by a facilitative transporter.

• Factors Affecting Net Rate of Diffusion:

  • Concentration Difference (A): The gradient between the outside and inside concentrations.

  • Electrical Potential Difference (B): Affects the movement of ions (specifically negative ions in common physiological models).

  • Pressure Difference (C): Physical force exerted by a piston or similar mechanism to cause diffusion of molecules and ions.

• Examples of Passive Facilitators:

  • Channel Proteins: Includes water channels (aquaporins), voltage-gated ion channels, ligand-gated ion channels, and mechano-sensitive channels.

  • Facilitative Transporters: The ubiquitous glucose transporter ($GLUT$) found in the plasma membrane of virtually all body cells.

Active Transport Mechanisms

• Primary Active Transport:

  • Requires direct energy expenditure via the hydrolysis of adenosine triphosphate ($ATP$).

  • The protein performing the transport is an $ATPase$, also referred to as a Pump.

  • Movement occurs against an electrochemical gradient.

  • Key Examples:

    • $Na^+/K^+/ATPase$ (ubiquitous sodium-potassium pump).

    • $H^+/ATPase$ (proton pump).

    • $H^+/K^+/ATPase$.

    • $Ca^{2+}/ATPase$ (calcium pump).

• Secondary Active Transport:

  • Utilizes the energy stored in the concentration gradient of a "driving ion" (typically $Na^+$ or $H^+$) rather than direct $ATP$ hydrolysis.

  • Couples the movement of the driving ion down its gradient to the movement of a separate molecule or ion against its concentration gradient.

  • Cotransport (Symport): The driving ion and driven molecule move in the same direction.

  • Exchange (Antiport): The driving ion and driven molecule move in opposite directions.

• Specific Secondary Active Transporters:

  • $SGLT1$ ($Na^+/\text{glucose cotransporter}$): Transports $21 Na^+$ ions and $11 \text{Glucose}$ molecule from extracellular to cytoplasmic space.

  • $NaPi lla/b$ ($Na^+/\text{phosphate cotransporter}$): Transports $31 Na^+$ ions and $11 P_i$ (inorganic phosphate).

  • $NIS$ ($Na^+/\text{iodide symporter}$): Transports $21 Na^+$ ions and $11 I^-$.

  • $NKCC$ ($Na^+/K^+/Cl^- \text{cotransporter}$): Transports $11 Na^+$, $11 K^+$, and $21 Cl^-$ ions.

  • $NCC$ ($Na^+/Cl^- \text{cotransporter}$): Transports $11 Na^+$ and $11 Cl^-$ ions.

  • $KCC$ ($K^+/Cl^- \text{cotransporter}$): Transports $11 K^+$ and $11 Cl^-$ ions.

  • Exchangers: $Na^+/H^+$ exchanger, $Na^+/Ca^{2+}/$ exchanger, and $Cl^-/\text{bicarbonate}$ exchanger.

Vesicular Transport: Endocytosis and Exocytosis

• Endocytosis: Specialized function for entering very large particles into the cell.

  • Pinocytosis: Ingestion of minute particles and extracellular fluid to form small vesicles inside the cytoplasm.

  • Phagocytosis: Ingestion of large particles such as bacteria, whole cells, or degenerating tissue.

  • Mechanism of Endocytosis:

    1. Molecules attach to specific receptors in coated pits.

    2. A latticework of fibrillar protein called clathrin, along with contractile filaments of actin and myosin, exists beneath these pits.

    3. The pit invaginates inward; fibrillar proteins cause borders to close over the proteins and extracellular fluid.

    4. The invaginated portion breaks away to form a pinocytotic vesicle.

• Phagocytosis Procedure (Step-by-Step):

  1. Phagocytes (white blood cells) are attracted to chemicals or debris from pathogens or abnormal cells.

  2. Phagocyte receptors bind to chemicals or antigens on the pathogen.

  3. The phagocyte changes shape to engulf the pathogen.

  4. A phagosome vesicle is formed containing the pathogen.

  5. A lysosome containing digestive enzymes fuses with the phagosome.

  6. Lysozyme (lytic enzyme) is released to hydrolyze the pathogen.

  7. The pathogen is destroyed.

  8. Soluble products are absorbed and used by the phagocyte.

• Exocytosis:

  • Active transport of large molecules from the interior to the exterior.

  • Vesicles fuse with the cell membrane to release contents; some fuse temporarily, others permanently.

  • Merocrine Glands: Glands that secrete products via exocytosis, such as sweat glands or neurotransmitter release at synapses.

Tonicity and Cellular Equilibrium

• Tonicity Types:

  • Isotonic: Relative concentration of non-penetrating solutes is equal inside and outside ($P=N$).

  • Hypertonic: Higher concentration of non-penetrating solutes outside the cell, causing cell shrinkage.

  • Hypotonic: Lower concentration of non-penetrating solutes outside the cell, causing cell swelling.

• Electrical Disequilibrium:

  • The separation of charged ions across the insulating membrane creates a potential.

  • Work/energy is used to pump cations out, creating a net negative charge inside (e.g., $-1$) and net positive outside (e.g., $+1$).

Quantitative Membrane Potential and The Nernst Equation

• Gibbs-Donnan Equilibrium: The behavior of charged particles separated by a semipermeable membrane where relative concentrations of permeable ions are shifted by the presence of an impermeable charged ion (like a protein).

• The Nernst Equation: Calculates the equilibrium potential ($V_{Eq.}$) for a single ion species.

$V_{Eq.} = \frac{RT}{zF} \times \text{ln} \frac{[X]_{out}}{[X]_{in}}$

• Variables Defined:

  • $V_{Eq.}$: Equilibrium potential (Nernst potential) (e.g., $V_K, V_{Na}, V_{Cl}, V_{Ca}$).

  • $R = 8.314 J.K^{-1}.mol^{-1}$ (Universal gas constant).

  • $T$: Temperature in Kelvin ($K = ^\text{o}C + 273.15$).

  • $z$: Valence of the ion ($+1$ for $Na^+$, $+2$ for $Ca^{2+}$, $-1$ for $Cl^-$).

  • $F = 96485 C.mol^{-1}$ (Faraday’s constant).

  • $[X]_{out}$: Extracellular concentration of ion $X$.

  • $[X]_{in}$: Intracellular concentration of ion $X$.

• Goldman-Hodgkin-Katz (GHK) Equation: Used to calculate membrane potential ($V_m$) when multiple ions are permeable.

$V_m = \frac{RT}{F} \text{ln} \frac{P_K[K^+]_o + P_{Na}[Na^+]_o + P_{Cl}[Cl^-]_i}{P_K[K^+]_i + P_{Na}[Na^+]_i + P_{Cl}[Cl^-]_o}$

Physiological Potentials and Action Potential Phases

• Resting Membrane Potential ($V_{rest}$):

  • Common value: $-70 mV$.

  • Maintained by the $Na^+/K^+$ transporter (pumping $Na^+$ out and $K^+$ in).

  • Voltage-gated $Na^+$ and $K^+$ channels are largely closed.

• Specific Ion Equilibrium Potentials:

  • $V_{Na} = +61 mV$

  • $V_{Cl} = -64 mV$

  • $V_{rest} = -68 mV$ to $-70 mV$

  • $V_K = -97 mV$

• Action Potential Phases:

  • Depolarization: In response to a stimulus, some $Na^+$ channels open. $Na^+$ enters the cell, making the internal charge less negative. If the threshold of excitation is reached, all $Na^+$ channels open.

  • Peak Action Potential: $Na^+$ channels close while $K^+$ channels open.

  • Hyperpolarization: $K^+$ leaves the cell, causing the membrane potential to drop below the resting level before stabilizing.