Cystic Fibrosis and
Membrane Transport
Cystic Fibrosis
CF causes the body to produce an abnormally thick,
sticky mucus on epithelial surfaces.
A genetic disease affecting approximately 30,000
children and adults in the United States.
It is one of the most common lethal inherited disorders
among caucasians
In 1997, the median survival age for males with CF
was 32.7 years versus 28.9 years in females
One in 31 Americans (one in 28 Caucasians) - more
than 10 million people - is an unknowing, symptom-
less heterozygous carrier of the defective gene
Source: Cystic Fibrosis Foundation
Symptoms and complications
Decreased mucociliary clearance of sputum leads to
chronic endobronchial bacterial colonization, and…
• Production of large amounts of sputum
• Wheezing
• Dyspnea
• Limited exercise tolerance
• Death
Pancreatic insufficiency in 85% of patients, leading to
malabsorption of fat and malnutrition.
Also diabetes mellitus, bowel obstructions, arthritis,
and infertility.
Fact 1: The phospholipid bilayer is a
selectively permeable barrier
Factors determining
the permeability of a
bilayer to a
molecule:
Size
Charge/polarity
Fact 2: There are concentration gradients across
the membrane for many molecules
Ion [inside] mM [outside]
Potassium 140 5
Sodium 10 145
Calcium 0.0001 1
Therefore…
If membranes are selectively permeable, and…
There exist concentration gradients of some
molecules, but not others, then…
There must be “transporters” that allow specific
solutes to cross the membrane, and…
Some solutes must be moved across actively.
What determines the direction a solute “wants”
to go?
Chemical gradient
• Solutes tend to move from more concentrated areas to less
concentrated areas
Electrical gradient
• Charged solutes tend to move towards an oppositely
charged environment
• Cells are universally more negative on the inside than the
outside. This membrane potential is typically ≈ -70 mV.
The combination of the two is called an
“electrochemical gradient”
ΔG for transport of x into a cell
xin
Gin RT ln
x zFVm
out
R = gas constant = 1.987 cal/mol/°K
T = absolute temperature in °Kelvin
F = Faraday constant = 23,062 cal/mol/V
z = charge on species
Vm = membrane potential in volts
Self test: What direction will K+ go?
Chemical gradient pushes out [K+] = 5 mM
• Inside = 140mM
• Outside = 5 mM
Electrical gradient pushes in [K+] = 140 mM
• Z = +1 Vm = -70 mV
• Vm = -70 mV = -0.07V
Body temp = 37ºC
R = gas constant = 1.987 cal/mol/°K
T = absolute temperature in °Kelvin
x F = Faraday constant = 23,062 cal/mol/V
Gin RT ln in zFVm
x
out z = charge on species
Vm = membrane potential in volts
The kind of transport you need depends on ΔG
Diffusion (ΔG 0)
• Primary
• Secondary
Facilitated diffusion (ΔG 5 mM
ΔGglucose IN = +1,418 cal/mol
ΔGsodium IN = -3,261 cal/mol
So one sodium CAN drive the import of one glucose from the
interior of your intestine!
Tight Junctions in epithelium
Functions:
1) Diffusion barrier
between cells
2) Segregates the
membranes
Apical vs. Baso-lateral
surfaces
Provides for
directional and
regulated transport
Cystic Fibrosis Transconductance
Regulator (CFTR)
A member of the ABC superfamily of transport proteins
However, it does not appear to act as an active transporter
A chloride channel – facilitated diffusion
Activated by phosphorylation
Permits chloride movement to the epithelial surface.
This results in osmotic flux of water to the apical surface,
diluting mucus.
In about 70% of CR cases, a mutated form of the CFTR is
reaches the ER, but is then degraded.
P
Basolateral
Cl- CFTR Cl-
Na+ Na+
Na+ Na+
K+
Apical
K+
H2O H2O
Basolateral
Cl-
Cl-
ER
Na+ Na+
Na+ Na+
K+
Apical
K+
H2O H2O
Current treatments
Treatment for Lung Problems
• Antibiotics
• Chest physical therapy (like percussion)
• Exercise
• Other medications
• Anti-inflammatory medications
• Bronchodilators,
• Mucus-thinning drugs
• Oxygen Therapy
Lung Transplantation
Management of Digestive Problems
• Oral pancreatic enzymes
• Fat-soluble vitamins A, D, E, and K
• Feeding tube
• Enemas and mucus-thinning medications to treat intestinal blockages
Brainstorm
What else might work?