PATH Cell Membranes

Midterm I

Cell Membrane

• Complex mix of lipids and proteins

• Essential for life and cellular functions

• Crucial in the creation of cellular compartments (inside/out, etc.)

• Selective barrier

Membrane Components

Lipids and Proteins

Membrane Lipids

• Make up 40-80% plasma + organelle membranes

• Phospholipids (most common), cholestrol, glycolipids

  • Major species of phospholipids: glycerophospholipids + sphingosine-based phospholipids (make up 4 most common phospholipids in animals/humans

    • Phosphatidylcholine (PC)

    • Phosphotidylserine (PS)

    • Phosphotidylethanolamine (PE)

    • Sphingomyelin (SM)

  • Amphipathic: polar hydrophillic head + nonpolar hydrophobic tails (different phospholipid species determined by polar head group, backbone composition, fatty chain composition)

  • Electrochemical differences of lipids determine membrane characteristics important to cell function

    • ex: RBC composed of 25% PC

Cholestrol

• Amphipathic

• Modulate phospholipids → interact with acyl groups (fatty acid hydrophobic chain)

Glycolipids

• Lipids w/ attached sugar residues

• Located in outer leaflet of the bilayer (face outside the cell)

  • Ex: Glycoalyx

• Functions: cell-cell interaction, gives (-) charge to cell surface, immune functions

Which component of a cell membrane phospholipid determines the makeup of the cell membrane and so is important for cell function?

Polar head group, acyl fatty acid tail, backbone composition

Fusion Events (Lipid Membranes)

• Endocytosis/exocytosis allow exchange and flow of lipids between organelles + plasma membrane by structural rearrangement of the plasma membrane

  • Endocytosis: active process, plasma membrane encloses a particle outside the cell → fuses to circumferentially engulf particle (ex: phagocytosis)

  • Exocytosis: active process, membrane bound vesicle from within the cell fuses to the plasma membrane → incorporating components of the membrane bound vesicle into the plasma membrane (ex: release of neurotransmitters)

Oxidative Damage + Repair (Membrane Lipids)

• Oxygen: highly reactive, will readily bond to fatty acyl groups of lipids

  • Polar: O bound to acyl renders more hydrophilic → bending towards head + destabilizes the membrane

    • Land’s Pathway: 3 enzymes protecting membrane from destabilization (phospholipase, acyl-CoA synthetase, acyl-CoA acyltransferase

      • Phospholipase (PLA2): cleaves damaged phospholipid from the membrane

      • Acyl-CoA synthetase (ACSL) + acyltransferase (LAT): allows generation of new phospholipid

Enzymatic Lipid Metabolism (Membrane Lipids)

• Phospholipase: classified based on ester bonds they cleave

  • hydrolyze phospholipids (normal steps in physiologic pathways)

  • important in signal transduction (ex: G-protein mediated signal transduction)

  • important in wound healing, inflammation, therapeutic targets against inflammation, cell signaling, vascular tone

    • Phospholipase A2 and eicosanoids

Movement: Fluidity and Mobility (Membrane Lipids)

• Lipids move by:

  • Rotation (spin in place)

  • Lateral movement (common, side-to-side)

  • Flip-flop (rare, across bilayer)

• Packing (lipid–lipid & lipid–protein interactions) affects mobility.

• Cholesterol slows lateral movement.

• Lipid organization supports processes (e.g., G-protein signaling).

• Distribution kept in tight equilibrium.

Reverse cholesterol transport

It’s the body’s way of cleaning up extra cholesterol.

• HDL (“good” cholesterol) picks up cholesterol from tissues (like blood vessel walls and cells).

• HDL carries this cholesterol back to the liver.

• The liver either reuses it (for making bile acids, hormones, membranes) or gets rid of it through bile.

👉 This process helps prevent cholesterol buildup in arteries, lowering the risk of atherosclerosis and heart disease.

Protein-Mediated Lipid Movement

• Lipids cross bilayer with protein help (hide hydrophobic tails).

• Examples:

  • Fatty acid binding proteins (acyl-CoA binding protein, albumin)

  • Lipid exchange proteins

• External sources also influence composition:

  • Ex: HDL ↔ RBC membrane lipid exchange

  • Changes in RBC lipids can signal liver disease / lipoprotein issues.

Lipid Exchange Proteins & Asymmetry

• Flippase & Scramblase maintain asymmetrical lipid distribution.

  • Flippase → inhibited by Ca²⁺ and oxidative damage.

  • Scramblase → activated by Ca²⁺.

• Dysfunction → abnormal phosphatidylserine (PS) exposure on outer leaflet.

• Consequences:

  • Early cell death (apoptosis signal).

  • Prothrombotic effect (PS exposure on RBC membrane promotes clotting).

Which of the following would result in membrane lipid turnover by producing major structural
rearrangement of the membrane?

a. Endocytosis
b. Lipid exchange proteins
c. Cholesterol packing
d. Hydrolysis by phospholipase

D

Integral Membrane Proteins

• Can’t be removed without disrupting the membrane (need detergents).

• Subtypes:

  • Transmembrane

    • Single-pass → one α-helix through bilayer.

    • Multipass → multiple passes (e.g., transporters, ion channels).

    • Example: Band 3 (RBC protein) → exchanges HCO₃⁻ for Cl⁻ to help CO₂ release in lungs.

  • Non-transmembrane

    • Anchored by covalent bond to a fatty acid or phospholipid.

    • Example: Acetylcholinesterase (important for neuromuscular function).

Peripheral Membrane Proteins

• Bound to polar head groups, fatty acid tails, or via sugar linkages.

• Can be removed without damaging the membrane.

Membrane Protein Movement

• Integral proteins are mobile, but movement can be slowed or restricted by:

  • Lipid–protein interactions

  • Protein–protein interactions

• Movements possible:

  • Lateral movement (side-to-side)

  • Rotation (spin in place)

  • ❌ No flip-flop → proteins cannot cross between membrane layers.

• Protein asymmetry is more rigid than lipid asymmetry.

• Example: Glycocalyx

  • “Fuzzy coat” of glycoproteins & glycosaminoglycans.

  • Always on outer monolayer.

  • Important for cell–cell communication & adhesion.

Clinical Case 1: Sickle Cell Anemia

• 7 y/o African American boy → population at risk for sickle cell disease (SCD).

• Triggers for sickling:

  • High altitude (Lake Tahoe) → lower oxygen → hypoxia.

  • Fever & infection (bacterial pneumonia) → increased metabolic demand, hypoxia, inflammation.

  • Dehydration → increased blood viscosity → promotes sickling.

• The combination of hypoxia (altitude + pneumonia), dehydration, and infection triggered widespread sickling of RBCs.

  • Primary driver = bacterial pneumonia → infection → hypoxia → acute chest syndrome, which further worsened oxygen delivery and perpetuated the hypoxia–sickling cycle.

  • Contributing factors = high altitude (less oxygen in environment) and dehydration.

Sickle Cell Disease (SCD)

• Genetic cause: Point mutation in the β-globin gene on chromosome 11 (not chromosome 16 — that’s for α-globin).

• Mutation changes hemoglobin A → hemoglobin S (HbS).

• HbS forms rigid, sickle-shaped red cells under low oxygen → hemolysis, anemia, vaso-occlusion.

  Main Forms of SCD

1. HbSS (Sickle Cell Anemia)

   • Inherited two HbS genes (one from each parent).

   • Most severe form of SCD.

   • Causes chronic hemolytic anemia, pain crises, organ damage.

2. HbSC

   • Inherited one HbS gene (from one parent) + one HbC gene (from the other parent).

   • Usually milder disease than HbSS.

   • Some protection against malaria.

3. HbS/β-Thalassemia

   • Inherited one HbS gene + one β-thalassemia gene.

   • Severity depends on type of β-thalassemia:

     • β⁰-thalassemia (no β-globin made) → severe, like HbSS.

     • β⁺-thalassemia (reduced β-globin) → milder disease.

Hemoglobin S - Effects on RBCs

1. Sickling

   • HbS polymerizes when oxygen is low → cells become rigid, “sickle-shaped.”

2. Membrane Stress & Damage

   • Sickling separates the lipid bilayer from the membrane skeleton.

   • This adds mechanical stress → membrane becomes fragile.

   • RBCs shed microparticles that expose phosphatidylserine (PS).

3. Oxidative Damage

   • HbS RBCs are less resistant to oxidative stress.

   • Ongoing damage injures both membrane lipids and proteins.

   • This overwhelms Land’s pathway (the cell’s membrane repair system).

4. Loss of Membrane Viability

   • Leads to Ca²⁺ influx and breakdown of normal phospholipid asymmetry.

   • Activates scramblase and inhibits flippase → more PS exposed.

5. Consequences of PS Exposure

   • Marks cells for early removal (hemolysis).

   • Makes RBCs vulnerable to phospholipase A₂ attack (from inflammation).

   • Promotes adhesion of RBCs to other cells or vessel walls → contributes to clotting imbalance and vaso-occlusion.

SCD - Clinical Outcomes of Molecular Events

1. Anemia

• Cause: Hemolysis occurs faster than bone marrow can replace red blood cells.

• Mechanism:

  • Exposed phosphatidylserine (PS) on sickled cells makes them targets for phospholipases, which accelerates breakdown.

• Result: Chronic hemolytic anemia with fatigue, pallor, jaundice.

2. Prothrombotic State (Increased Clotting Risk)

• Cause: Sickled RBCs expose PS, which acts like platelets in the clotting cascade.

• Mechanism:

  • PS exposure makes RBCs sticky → they adhere to other cells and vessel walls.

  • Promotes abnormal clot formation.

• Result:

  • Stroke-like events

  • Infarction (tissue death due to blocked blood supply)

  • Renal damage

3. Pro-inflammatory State

• Cause: Hemolysis releases free hemoglobin and heme into circulation.

• Mechanism:

  • Free Hb and breakdown products are toxic and pro-inflammatory.

  • They trigger systemic inflammation.

• Result:

  • Pain crises

  • Worsening vascular damage

  • Risk of multiorgan failure in severe cases

Malaria and Sickle Cell Disease

• Malaria is a disease caused by the protozoan
  parasite Plasmodium falciparum (and others)
  which is transmitted by mosquitos

• The merozoite stage infects the red cell by
  invasion through the cell membrane and
  multiple life stages of the parasite develop
  within the cytoplasm of the red blood cell

• Development of these stages requires use of
  the host cell, including the cell membrane

• Any disorder of the red cell membrane or
  other necessary components of the
  parasites life cycle make the host
  resistant to disease

Clinical Case 2 - Malaria

Patient: 26-year-old man, returned from West Africa 3 weeks ago

Symptoms:

• Trouble breathing (worse over a week)

• Fever

• Yellow skin/eyes (jaundice)

Exam:

• Mild jaundice

• Crackling sounds in lungs

• Breathing very fast (33/min)

• Low oxygen (87%, normal 95–100%)

• High fever (39.8°C)

Problem List

• Jaundice (from red blood cell breakdown or liver problem)

• Possible pneumonia (lung crackles, cough, low oxygen)

• Low oxygen (hypoxia)

• Fever

Lab Results

• Anemia: low hematocrit (32.2%, normal 41–50%)

• Low platelets: 78,000 (normal 150–400k)

• High bilirubin: 4.2 (normal 0.1–1.2) → explains jaundice

• High creatinine: 2.2 (normal 0.7–1.3) → kidney stress/damage

• Blood smear: Plasmodium falciparum (malaria parasite) inside red blood cells

Summary

This patient has severe malaria (Plasmodium falciparum) with:

• Anemia (RBC destruction)

• Jaundice (from breakdown of RBCs)

• Low platelets (bleeding risk)

• Kidney problems (high creatinine)

• Lung involvement (trouble breathing, low oxygen, crackles)

What does hemoglobin S to do a red blood cell?
a. Results in polymerization of the plasma membrane at low oxygen saturation
b. Results in exposure of PS
c. Dysregulation of asymmetry of phospholipids
d. Decreased repair of oxidative damage
e. All the above

e. All of the above

Flippase is _______ by increased intracellular calcium concentrations and scramblase is
____________
a. Inhibited, inhibited
b. Inhibited, activated
c. Activated, inhibited
d. Activated, activated

B. Inhibited, activated

Membrane Transport - Diffusion

Definition

• Movement of small, uncharged particles from high → low concentration.

• Goal: reach equilibrium on both sides of the membrane.

Factors Affecting Diffusion (Fick’s First Law)

• Surface area of the membrane

• Concentration gradient (difference across membrane)

• Diffusion coefficient (how easily the particle crosses)

Modification for plasma membranes:

• Membranes have a hydrophobic core → particle must dissolve in lipid.

• Permeability coefficient accounts for lipid solubility.

Diffusion of Hydrophilic or Charged Particles

• Movement is influenced by both:

  • Concentration gradient (high → low)

  • Electrochemical gradient (charge differences across the membrane)

Membrane Transport - Osmosis

Definition

• Movement of water across a membrane from low solute concentration → high solute concentration.

• Water cannot cross a lipid bilayer efficiently without aquaporins (special membrane water channels).

Key Concepts

• Water movement creates pressure.

• Osmotic pressure = pressure needed to stop water from moving across the membrane.

• Determined by:

  • Number of particles in solution

  • Degree of ionization of particles

• Osmosis continues until an isotonic state (equilibrium) is reached.

• Red blood cell cytosol tonicity: ~286 mOsm

Comparing Solutions

• Isotonic: Osmotic pressures are equal → no net water movement

• Hypotonic: Osmotic pressure is lower → water moves into the cell

• Hypertonic: Osmotic pressure is higher → water moves out of the cell

Donnan Effect (Osmosis)

Definition

• Water movement across a membrane is affected not just by solute concentration, but also by the charge of solutes.

• This is called the Donnan effect.

Key Concepts

• When charged solutes reach electrical equilibrium, water moves to achieve isotonicity.

• The inside of the cell is negatively charged (from RNA and proteins).

• This causes a net influx of water into the cell due to the Donnan effect.

• Cells counteract this by actively pumping out ions to prevent swelling (hypotonicity).

Membrane Transport - Facilitated Diffusion

Definition

• Some particles diffuse very slowly across membranes because they cannot pass through the lipid bilayer easily (low permeability).

• Facilitated diffusion uses transmembrane proteins (channels or carriers) to speed up transport.

Key Points

• Rate of transport depends on protein binding rules (e.g., how many molecules a transporter can move at once).

  • Example: D-glucose is transported into RBCs efficiently, but L-glucose is not.

• Energy not required → still considered passive transport.

• Useful for moving hydrophilic or larger molecules that cannot diffuse freely.

Membrane Transport - Active

Definition

• Active transport moves molecules against their concentration gradient.

• Energy is required, usually from ATP.

1. Primary Active Transport

• Uses energy directly from ATP to move particles against their gradient.

• Example: Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in per ATP molecule.

2. Secondary Active Transport

• Uses energy from the movement of one particle down its gradient to move another particle against its gradient.

• Types:

  • Symport: both particles move in the same direction

  • Antiport: particles move in opposite directions

• Example: Absorption of glucose and amino acids in the gastrointestinal tract.

Which form of membrane transport relies on aquaporins?
a. Facilitated diffusion
b. Osmosis
c. Primary active transport
d. Secondary active transport

b. Osmosis

Membrane Transport - Ion Channels

Key Points

1. Purpose

• Some ions cannot cross the lipid bilayer on their own (they’re “immiscible” with the fatty core).

• Ion channels provide a path, allowing ions to cross 100–1000× faster than facilitated diffusion.

• This speed is essential for neurons and muscle cells.

2. Direction of Ion Movement

• Channels do not set direction.

• Direction is determined by:

  • Concentration gradient (high → low)

  • Electrical potential across the membrane

3. Structure of Ion Channels

• Made of hydrophobic regions that span the lipid bilayer.

• Hydrophilic regions line the channel, forming a pathway for ions.

• Example: Acetylcholine receptor

  • Hydrophobic α-helices span the membrane.

  • Hydrophilic residues point inside the channel, allowing ions to pass.

Ion Channel Gating

Gating = the opening and closing of ion channels in response to specific stimuli.

Types of Gated Ion Channels

1. Voltage-gated

   • Open/close in response to changes in electrical potential across the membrane.

   • Example: Nerve impulses and communication between nerves and muscles.

2. Ligand-gated

   • Open/close when a chemical ligand binds reversibly to the channel.

   • Example: Acetylcholine receptor at synapses.

3. Mechanically gated

   • Open when the cell is physically deformed.

   • Changes in the cytoskeleton affect the channel’s shape.

4. Gap junction channels

   • Allow ions to flow directly between cells, bypassing extracellular space.

   • Stimulus: changes in calcium or hydrogen ion concentration.

Membrane Potential

Definition

• The membrane potential (Vm) is the voltage difference across a cell’s membrane.

• Formula: Vm = Vi – Vo

  • Vi = voltage inside the cell

  • Vo = voltage outside the cell

• At rest, Vm is negative due to negatively charged cytoplasm.

• Most important in excitable cells like neurons and muscle fibers.

Key Ions Involved

• Na⁺: high outside the cell

• K⁺: high inside the cell

• Cl⁻: high outside the cell

• Organic anions (e.g., amino acids): high inside the cell

• K⁺ leak channels allow K⁺ to flow freely → maintains resting membrane potential.

Equilibrium Potentials

• Equilibrium potential = voltage at which there is no net movement of an ion.

• Calculated with the Nernst equation:

  • Example for K⁺:

    EK=RTZFln⁡[K+]o[K+]iE_K = \frac{RT}{ZF} \ln\frac{[K^+]_o}{[K^+]_i}EK​=ZFRT​ln[K+]i​[K+]o​​

  • For most mammalian cells: Eₖ ≈ –96 mV

• Membrane potential at rest (Vr) is close to Eₖ (~–80 to –90 mV) because the membrane is most permeable to K⁺.

Na⁺ Potential

• ENa ≈ +67 mV

• Na⁺ is pumped out by Na⁺/K⁺-ATPase, but closed channels prevent influx at rest.

• Na⁺ wants to enter the cell due to concentration and electrical gradients, but cannot until channels open.

Electrical Signals in Cells

• Changes in ion movement toward their equilibrium potential create electrical signals.

• Neurons:

  • Na⁺ influx depolarizes the membrane → inside becomes less negative.

  • This generates an action potential, which propagates along the neuron.

✅ Summary:

• Resting cells are negative inside, mostly due to K⁺.

• Membrane potential depends on ion gradients and permeability.

• Ion flow toward equilibrium potentials allows cells to signal and respond (e.g., nerve impulses, muscle contraction).

Neuronal Membrane Potential

Depolarization

• Influx of Na⁺ into the neuron makes the inside less negative.

• This occurs through voltage-gated sodium channels.

• The initial depolarization spreads as a current, but weakens as it moves due to K⁺ leak channels.

Propagation of the Signal

• Neurons have a special structure to carry signals from dendrites → axon.

• Axon hillock: voltage-gated Na⁺ channels here trigger a self-propagating depolarization.

• This chain reaction continues down the axon, allowing the nerve signal to travel long distances.

✅ Key Point:

• Depolarization starts at the dendrites/axon hillock and is propagated down the axon by voltage-gated Na⁺ channels, with K⁺ leak channels helping reset the membrane.

Returning to Resting Membrane Potential

After a neuron depolarizes, two main mechanisms restore the resting membrane potential:

1. Rapid closure of voltage-gated Na⁺ channels

   • Stops Na⁺ from entering the cell.

   • These channels become temporarily inactivated, preventing immediate reopening.

2. Opening of voltage-gated K⁺ channels

   • Open slowly, usually near the peak of the action potential.

   • K⁺ flows out of the cell, repolarizing the membrane (making inside more negative again).

✅ Key Point:

• Na⁺ channels close → stops further depolarization

• K⁺ channels open → restores the negative resting potential

Action Potential Propagation

Speed Factors

• Action potentials travel faster when:

  • Axon diameter is larger

  • Axon is insulated with myelin

Myelin and Nodes of Ranvier

• Myelin sheaths: lipid-rich layers around axons made by oligodendrocytes (CNS) or Schwann cells (PNS).

• Internode: the myelinated segment of the axon.

• Nodes of Ranvier: gaps between myelin sheaths.

  • Voltage-gated channels are concentrated here.

  • Action potentials jump from node to node (saltatory conduction), increasing speed and efficiency.

Clinical Relevance

• Demyelinating diseases (e.g., Multiple Sclerosis) damage myelin.

  • This slows or stops nerve signal conduction.

  • Results in sensory and motor dysfunction.

✅ Key Point:

• Myelin + nodes = faster, more efficient nerve signal propagation.

• Loss of myelin = slower or blocked signals.