Facilitated Diffusion

Definition

Key Characteristics

Mechanism (Carrier-Mediated)

1. The molecule enters a pore in the carrier protein and binds to a receptor site.
2. A conformational change occurs in the carrier protein - the pore flips to open on the opposite side of the membrane.
3. The weak binding is overcome by thermal motion, and the molecule is released on the other side.
4. The carrier returns to its original conformation and the cycle repeats.

• Guyton and Hall Textbook of Medical Physiology, p. 68

Rate vs. Concentration: The Vmax Concept

• At low concentrations: facilitated diffusion is faster than simple diffusion (the carrier "helps").
• At high concentrations: all carrier binding sites are occupied (saturated), and the rate plateaus at Vmax. Simple diffusion has no such ceiling.

Properties of Carrier-Mediated Transport (shared with active transport)

1. Specific binding site for the solute
2. Saturation - there is a finite Vmax
3. Km - the transporter has an affinity constant for its substrate (like an enzyme)
4. Competitive inhibition - structurally similar molecules compete for the same binding site

• Harper's Illustrated Biochemistry, 32nd Ed, p. 2502

Types of Transporter Systems

Key Examples

• At least 14 members of the GLUT family have been identified.
• GLUT4 is found in skeletal muscle, adipose tissue, and heart.
• Insulin stimulates translocation of GLUT4 from intracellular vesicles to the plasma membrane, increasing glucose uptake 10-20 fold.
• D-galactose and phlorizin competitively inhibit glucose transport via GLUT4.
• The non-physiologic stereoisomer L-glucose is NOT transported (demonstrates stereospecificity).

• Most amino acids cross cell membranes via carrier-mediated facilitated diffusion or Na⁺-dependent active transport.

• Absorbed at the apical membrane of intestinal epithelium via facilitated diffusion (GLUT5).

• Facilitated diffusion is common in eukaryotic microorganisms (e.g., yeast) but rare in prokaryotes.
• Glycerol is one of the few molecules transported by facilitated diffusion in bacteria.

Transporters vs. Ion Channels

• Harper's Illustrated Biochemistry, 32nd Ed

Summary

Secondary Transport - Simple Explanation

The Big Idea: "Riding on Na⁺'s Back"

• The Na⁺-K⁺ pump (primary active transport) uses ATP to constantly push Na⁺ out of the cell. This creates a high Na⁺ concentration outside and low concentration inside.
• This is like charging a battery - energy is now stored in that Na⁺ gradient.
• Secondary transport uses that stored energy to move another molecule. No ATP is needed directly!

The Two Types

1. Cotransport (Symport) - "Both go IN together"

• The SGLT carrier has two binding sites - one for Na⁺, one for glucose.
• Both must bind for the carrier to rotate.
• Na⁺ flows in down its gradient → glucose gets carried in too, even against its own concentration gradient.
• This is how your intestine absorbs glucose from food and your kidney rescues glucose from urine.

• Na⁺ + amino acids (intestine and kidney)
• Na⁺ + K⁺ + 2Cl⁻ (NKCC transporter in kidney thick ascending limb)

2. Countertransport (Antiport/Exchange) - "One goes IN, other goes OUT"

• Na⁺ enters the cell → Ca²⁺ is pushed out of the cell.
• This keeps intracellular Ca²⁺ low (important for heart muscle relaxation).

• Na⁺ enters → H⁺ is pushed out.
• Important for regulating cell pH and kidney acid secretion.

The Full Picture: How it all connects

1. Luminal (apical) side: SGLT1 cotransports Na⁺ + glucose into the cell from the gut.
2. Basolateral side: Na⁺-K⁺ ATPase uses ATP to pump Na⁺ out (keeps intracellular Na⁺ low, maintaining the gradient for SGLT1). Glucose exits by facilitated diffusion (GLUT) into the blood.

The Na⁺-K⁺ pump is constantly "recharging the battery" that powers SGLT.

What Happens if You Block the Na⁺-K⁺ Pump?

• Intracellular Na⁺ rises → the gradient disappears → SGLT and all other secondary transporters stop working.
• This shows that all secondary transport indirectly depends on ATP, just not directly.
• Costanzo Physiology 7th Edition, p. 17-18

Quick Summary Table

Primary transport = uses ATP directly. Secondary transport = uses the gradient ATP already built.

Homeostasis - The Body's "Stay Normal" System

Definition

• Body temperature (37°C)
• Blood glucose levels
• Blood pressure
• Blood pH (7.35-7.45)
• Na⁺, K⁺, Ca²⁺ concentrations
• Oxygen and CO₂ levels

"Homeostasis is the control of a vital parameter." - Medical Physiology (Boron & Boulpaep)

The 4 Parts of Any Homeostatic System

1. Negative Feedback - "The CORRECTOR" ✅

Simple Idea:

When something goes too high, the body brings it down. When something goes too low, the body brings it up. It opposes (goes negative to) the change. That's why it's called negative.

Easy Analogy: Room Thermostat

• You set the thermostat to 25°C (set point).
• Room gets too hot → thermostat turns on AC → room cools down.
• Room gets too cold → thermostat turns on heater → room warms up.
• In both cases, the system corrects back to 25°C.

Medical Example 1: Blood Glucose

You eat food
    ↓
Blood glucose RISES above normal
    ↓
Pancreas SENSES the rise (sensor)
    ↓
Pancreas releases INSULIN (effector)
    ↓
Cells take up glucose → blood glucose FALLS back to normal
    ↓
Insulin release STOPS (feedback loop complete)

Medical Example 2: Blood CO₂

• CO₂ rises in blood → chemoreceptors detect it → brain tells lungs to breathe faster → more CO₂ is expelled → CO₂ returns to normal.
• CO₂ falls too low → breathing slows down → CO₂ builds back up.

Key Point: Gain

2. Positive Feedback - "The AMPLIFIER / FINISHER" 🔁

Simple Idea:

When something goes up, the body makes it go even higher. It pushes in the same direction - amplifying the change instead of correcting it. It does NOT return to a set point. Instead it builds and builds until a task is completed, then stops.

Easy Analogy: Microphone Feedback

Medical Example 1: Childbirth (Labour)

Baby's head pushes on cervix
    ↓
Cervix stretches → signals sent to brain
    ↓
Brain releases OXYTOCIN
    ↓
Oxytocin causes stronger uterine contractions
    ↓
Stronger contractions push baby harder against cervix
    ↓
Even MORE oxytocin released...
    (keeps amplifying)
    ↓
Baby is BORN → stretch stimulus removed → cycle ends ✅

Medical Example 2: Blood Clotting

Blood vessel is injured
    ↓
A small amount of thrombin (clotting factor) is formed
    ↓
Thrombin triggers MORE thrombin formation
    ↓
More thrombin = more clot formation
    ↓
Clot grows rapidly until the wound is sealed ✅
    ↓
Bleeding stops → positive feedback ends

"In each case in which positive feedback is useful, the positive feedback is part of an overall negative feedback process." - Guyton and Hall Textbook of Medical Physiology

Positive Feedback Gone Wrong: Vicious Cycles ⚠️

• Haemorrhagic shock: Losing blood → heart gets weaker → pumps less blood → organs get less oxygen → heart gets even weaker → more blood loss... → death.
• The body loses 2+ litres of blood without intervention → this vicious cycle cannot be stopped on its own.

Side-by-Side Comparison

One-Line Memory Tricks

• Negative feedback = "Fix it and calm it down" (like a THERMOSTAT 🌡️)
• Positive feedback = "Keep going until the job is done" (like a DOMINO effect 🁢)
• Guyton and Hall Textbook of Medical Physiology, pp. 25-28
• Medical Physiology (Boron & Boulpaep), p. 16

How Insulin Helps Glucose Enter Cells

The Basic Problem First

Step 1: First, How is Insulin Released?

1. Glucose enters the pancreatic beta cell via GLUT transporters
2. Glucose is metabolised → ATP is produced
3. High ATP closes K⁺ channels → cell membrane depolarises
4. Depolarisation opens Ca²⁺ channels → calcium floods in
5. Calcium triggers insulin secretion from secretory granules

Step 2: Insulin Travels to Target Tissues

• Skeletal muscle (biggest glucose consumer)
• Adipose tissue (fat cells)
• Liver

Step 3: Insulin Binds to Its Receptor - The Signal Cascade

Insulin binds to Insulin Receptor (α subunit)
        ↓
Receptor's β subunit activates its own Tyrosine Kinase
        ↓
Receptor AUTO-phosphorylates itself (turns itself ON)
        ↓
IRS proteins (Insulin Receptor Substrates) get phosphorylated
        ↓
IRS activates PI3-Kinase (PI3K)
        ↓
PI3K makes PIP3 (a lipid messenger)
        ↓
PIP3 activates PDK-1
        ↓
PDK-1 activates Akt2 (PKB)
        ↓
Akt2 signals GLUT4 vesicles to MOVE to the cell surface
        ↓
GLUT4 transporters appear on the plasma membrane 🚪
        ↓
Glucose flows IN via facilitated diffusion ✅

• Harrison's Principles of Internal Medicine 22E, p. 3242
• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 1046

Step 4: Once Inside - What Happens to Glucose?

The GLUT Family - Different Doors for Different Tissues

• Tietz Textbook of Laboratory Medicine, 7th Ed

Simple Analogy - The Parking Garage

• No insulin → garage door is shut → cars (GLUT4) stay inside → glucose cannot enter the cell
• Insulin arrives → garage door opens → cars (GLUT4) drive out to the street (plasma membrane) → glucose can now enter freely

What Goes Wrong in Diabetes?

One-Line Summary

Insulin binds its receptor → activates PI3K → Akt2 → GLUT4 moves from inside the cell to the cell surface → glucose enters by facilitated diffusion → blood sugar drops. ✅