20260311_dn_CELL MEMBRANE STRUCTURE AND FUNCTION_ TRANSPORT ELECTRICAL PROPERTIES

What are the components and the function of the lipid bilayer?
How can membrane components be associated and confined to specific domains within a membrane?
What is the difference between channels and transporters?
What is active membrane transport?
What are chemical synapses?

General Overview:
- Biological membranes surround cells (plasma membrane) and organelles (ER, Golgi, mitochondria, nucleus).
- Structure:
- Double layer approximately 5 nm thick, relatively impermeable to water-soluble molecules.
- Composition: Thin film of lipids and proteins held together by noncovalent interactions.
- Composition:
- Lipids comprise approximately 50% of membrane mass (~10^9 molecules per cell).
- Phospholipids are the most abundant: phosphoglycerides, sphingolipids, and sterols.
- Most membrane proteins span the lipid bilayer and function as sensors/receptors to transfer information across the membrane.
- Types of membrane proteins: Channels, transporters, enzymes, anchors.
Clinical Relevance:
- Membrane defects are responsible for diseases such as hereditary spherocytosis (red blood cell membrane protein defects), cystic fibrosis (Cl⁻ channel CFTR), and familial hypercholesterolemia (LDL receptor).

Phospholipid Structure:
- Lipid molecules are amphiphilic, possessing both hydrophobic and hydrophilic parts.
- Typical phospholipid molecule and sterol molecule structure features:
- Hydrophilic head group:
  - Choline: CH2-N+(CH3)₃, Phosphate: O=P-O.
- Hydrophobic tails:
  - Composed of fatty acid chains.
Major Phospholipids in Mammalian Plasma Membranes:
- Phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine, sphingomyelin.

Phospholipids spontaneously form bilayers in water to avoid hydrophobic interactions with water.
Shape Interaction:
- Cone-shaped lipids form micelles, whereas cylindrical-shaped lipids form bilayers (most phospholipids).
Bilayers self-seal, creating closed compartments that avoid exposure of hydrophobic tails to water, a thermodynamically favorable configuration.
Clinical Applications:
- Liposomes (artificial bilayer vesicles) as drug delivery vehicles (e.g., liposomal doxorubicin for cancer treatment).

Fluid Nature:
- The lipid bilayer is a two-dimensional fluid allowing rapid lateral diffusion of lipids (~2 μm/sec), but flip-flopping between monolayers occurs very rarely and is slow.
Phospholipid Synthesis:
- Primarily occurs on the cytosolic face of the endoplasmic reticulum (ER).
- Flippases catalyze the flip-flop of phospholipids to maintain bilayer asymmetry.
- Cholesterol does not require translocators and can flip rapidly between monolayers.
Clinical Implication:
- Loss of flippase activity can lead to conditions such as Scott syndrome, which results in abnormal blood clotting due to phosphatidylserine exposure on the outer membrane during apoptosis (serving as an “eat me” signal for phagocytes).

Membrane Fluidity Factors:
- The fluidity of lipid bilayers depends on composition and must be regulated.
- Factors Increasing Fluidity:
- Shorter hydrocarbon chains.
- More cis-double bonds (creating kinks).
- Lower cholesterol content at high temperatures.
- Role of Cholesterol:
- At high temperatures, cholesterol reduces fluidity; at low temperatures, it prevents solidification.
Membranes contain between 500-2000 different lipid species. Inositol phospholipids, present in small amounts, play crucial roles in signaling and cell migration.
Clinical Connection:
- Membrane fluidity affects drug absorption and anesthetic action; e.g., general anesthetics like halothane alter membrane fluidity, potentially affecting their mechanisms of action.

Lipid Rafts:
- Nanoclusters of cholesterol, sphingolipids, and specific proteins create thicker, liquid-ordered membrane regions, enriching in GPI-anchored proteins and some transmembrane proteins.
- Rafts concentrate signaling molecules for efficient transduction and are reinforced by weak interactions amongst proteins and lipids.
- Clinical Relevance:
- Pathogens exploit lipid rafts for entry into cells (e.g., HIV, influenza, cholera toxin).
- Statins may disrupt rafts, thus reducing viral entry.

Lipid droplets are surrounded by a unique phospholipid monolayer.
Adipocytes specialize in lipid storage, storing neutral lipids (triacylglycerols, cholesterol esters).
Lipid droplets form rapidly when cells are exposed to high-fatty acid concentrations and are recognized as dynamic organelles with regulatory functions.
Clinical Impact:
- Dysfunctional lipid droplets have been linked to obesity, fatty liver disease (NAFLD/NASH), atherosclerosis, and lipodystrophies.

Lipid Bilayer Composition:
- Asymmetric, with different compositions in the two monolayers.
- Outer Leaflet: Phosphatidylcholine (PC), sphingomyelin (SM).
- Inner Leaflet: Phosphatidylserine (PS), phosphatidylethanolamine (PE).
The asymmetry has functional importance:
- PS and inositol phospholipids serve as docking sites for cytosolic signaling proteins (PKC, PI3K, PLC).
- Asymmetry helps cells distinguish between live and dead cells during apoptosis (e.g., PS exposure as a signal for macrophages).
Clinical Implication:
- Annexin V binds PS and is used clinically to detect apoptosis. Autoantibodies against membrane phospholipids can cause conditions like thrombosis and pregnancy loss.

Glycolipids are found on the surface of all eukaryotic plasma membranes, derived from sphingosine, and make up approximately 5% of total lipid.
Functions include protection against harsh conditions and cell