June 9 - Part 3 Lipid Rafts and Membrane Transport Notes

Lipid rafts are areas in the cell membrane with higher cholesterol density and tighter lipid packing.
They appear as if rafts are floating on the cell surface.
These areas are dynamic, with proteins moving in and out.
Glycoproteins, glycolipids, and glycosphingolipids on the raft's exterior help it float.
Over 200 different proteins are associated with lipid rafts.
Rafts interact with the cytoskeleton and are organized by the underlying cell structure.
Damage to rafts affects proteins, cell recognition, and other cellular functions.
Rafts are associated with several diseases.
They respond to external signals, especially in the immune system.
Rafts concentrate and move ions across cell membranes, helping immune cells target the cell.
They can transport toxins (e.g., cholera) into the cell via receptors.
Rafts can be anchored and contain enzymes that activate cell components.
Associated with neurodegenerative diseases (Alzheimer's, Parkinson's), diabetes, and cardiovascular diseases.
They can serve as pharmacological targets.

Involved in peripheral nervous system repair.
Changes to rafts are seen in stroke; altering rafts can impair cell repair and affect patient condition.
Serve as a guidance system for axon growth in the peripheral nervous system.
Guide cell repair after injury and are involved in inflammation.
Changes in the raft facilitate nerve cell repair; blocking the raft prevents nerve regeneration.

Proteins move laterally in the cell membrane.
Proteins do not typically "flip-flop" from one side of the membrane to the other; this is more common with lipids via flipases (inside to outside) and flopases (outside to inside).
Restricting protein movement limits the diffusion of materials across membranes.
Membranes anchor the cytoskeleton; losing this anchoring can change cell shape (e.g., sickle cell anemia).
Anchoring allows cells to withstand stress, such as starvation.
The body enters starvation mode approximately every three hours, requiring the breakdown of cell components.

Patient presents with high blood sugar in the morning despite taking insulin and metformin.
It's normal for blood sugar to be higher in the morning.
Explanation:
- Glucose from dinner is stored in the liver and muscles.
- The body needs energy while asleep, even without eating.
- During sleep, the body enters starvation mode, breaking down cell components and requiring glucose.
- The brain needs glucose, so the body makes it.
- The liver breaks down glycogen to glucose, and muscles break down fatty acids and amino acids.
- This process alters membranes.
- Growth hormone stimulates glucose production.
- Result: Elevated blood glucose levels upon waking.
Advice to the patient:
- Consider a snack with complex carbohydrates before sleep to help stabilize blood glucose levels overnight; this relates to the interaction of the cell membrane and lipid rafts in glucose utilization.

Insulin lispro: Rapid-acting.
Intermediate-acting insulin: Effective for 4-12 hours.
Insulin glargine: Long-acting, effective for 24 hours.
Long-acting insulin is used to maintain stable insulin levels overnight where shorter acting are before meals.

Membranes are asymmetric, with different compositions on the outside and inside.
Carbohydrates are primarily on the outside of the cell.
Asymmetry is established in the endoplasmic reticulum (ER) and Golgi apparatus.
The ER and Golgi dictate where the membranes will go (peroxisome, lysosome, cell exterior).

Apical cell surface: The top of the cell.
Basal cell surface: The bottom of the cell.
Lateral surfaces: The sides of the cell, divided into upper and basolateral regions.
The upper lateral region has cell junctions, while the basolateral region is involved in biochemistry and transport.
The apical region may have a brush border or microvilli (specialized for absorption or enzyme activity).
Cilia and flagella are also present.
Caveolae: Invaginations in the cell membrane (e.g., in intestinal cells) to increase surface area and specialize in transport.

Patient presents with blurry vision upon waking, with no prior symptoms.
Differential diagnosis: Elevated blood sugar, diabetes.
Blurred vision associated with elevated blood sugar levels can indicate the need to see an ophthalmologist.

Passive transport: Simple diffusion, facilitated diffusion, filtration, osmosis, dialysis.
Active transport: Primary, secondary, endocytosis, exocytosis.

The concept of tonicity is based on the comparison of non-penetrating particles; water movement is based on tonicity.
Isotonic: Equal number of non-penetrating particles on both sides of the membrane.
Hypertonic: One side has more non-penetrating particles.
Hypotonic: One side has fewer non-penetrating particles.

Molecules move to unoccupied spaces.
Selective permeability: The membrane controls what can pass through.
Hydrophobic/lipid molecules and some gases cross easily.
Charged particles do not cross easily; higher charge means less transport. Small non-polar molecules cross.
Oxygen, nitrogen, glycerol, CO2, and water can cross. Large molecules cannot, however alcohol, benzene, carbon dioxide and oxygen diffuse across the membrane.
Glucose and charged ions usually require channels.

Fick's Law:
- Temperature: Higher temperature = faster diffusion.
- Size: Smaller molecule = faster diffusion.
- Charge: Non-charged particles diffuse more readily.
- Equilibrium: Diffusion occurs until equilibrium (concentration or charge) is reached.
- Area: greater the area the faster the rate of diffusion.
- Thickness: The thinner the area the faster the rate of diffusion.

Bronchitis/COVID/Pneumonia: Fluid (phlegm, water) increases the distance for diffusion, slowing it down.
Alveolar membrane and blood vessel are fused.
Increased distance reduces oxygen diffusion into the blood, causing breathing difficulties.
Oxygen therapy increases the concentration gradient to improve diffusion.
Size, lipid solubility, membrane surface area, and charge all affect diffusion.

Bioavailability: The availability of a drug in the bloodstream.
Drugs are typically small, charged, and require lipid solubility to cross membranes.
pKa:
- The inherent charge on a molecule.
- When pH = pKa, the chemical or drug is 50% charged.
- Acid drugs in acid environments are less charged and vice versa.
Henderson-Hasselbalch Equation:
- $pH = pKa + log(\frac{Base}{Acid})$
- Predicts the ionized form of the drug based on environmental pH and drug pKa
Acid drugs are absorbed better in acid environments, and basic drugs in basic environments.
Aspirin (pKa = 3.5) is better absorbed in the acidic stomach.

Patient on penicillin for a nervous system infection (acid environment): The antibiotic crosses the blood-brain barrier.
Stopping antibiotics early: As the infection improves, the environment becomes less acidic, reducing penicillin absorption, potentially causing a relapse.
Tooth Abscess: Anesthetics (basic) don't work well in an acidic, infected environment. Administer antibiotics first to increase the local pH before using anesthetics.