3 Membrane Transport

• • PM has very selective permeability
• • gasses are considered hydrophobic - can easily cross
• • polar molecules diffuse through at such a slow rate that it’s not useful to the cell to achieve concentration gradient it needs
• • ions have NO WAY of diffusing through the membrane
• • main reason for membrane: to have separate compartments with different molecule concentrations inside & out

1. Simple Diffusion

• 2. Passive Transport (Channel or Carrier-mediated)
• - E for this type of transport comes from moving a molecule down its gradient

3. Active Transport (takes ENERGY)

• • moves glucose down it’s chemical gradient (from high to low concentration)
• • glucose binds to a very specific binding site on permease (only right kind of sugar can bind)
• • the energy of it binding creates a conformational change that opens a channel
• • glucose passes through the channel & is released into the cytoplasm
• • the release causes another conformation change & the permease reverts to its original conformation where it can accept more glucose molecules

it speeds up diffusion by about 100 fold

• • usually mediated by carrier proteins
• • is still Passive - doesn’t require energy because it’s using the energy created by 1 molecule going down its gradient to move the other molecule UP it’s gradient (chemical OR electrochemical)

• move solutes together in the same direction, 1 up & 1 down their concentration gradient

• eg. Na⁺/Glucose cotransporter: couples the downhill movement of Na⁺ into epithelial cells with the uphill movement of glucose into epithelial cells

• moves solutes in opposite directions, again 1 up & 1 down its concentration gradient

• eg. Band 3 anion antiporter (anion exchanger, typically bicarbonate for chloride)

• start moving the molecule going down it’s gradient 1st to generate the energy to move the other molecule in the opposite direction

• Na⁺ → low inside, high outside
• K⁺ → high inside, low outside

• • moves 3 Na⁺ out of cell to bring in 2 K⁺ into the cell using ATP
• • whenever a molecule is burning ATP to do transport it’s called a PUMP → means there’s ATP cleavage involved

• it’s like an antiporter in that both molecules are going in opposite directions however it isn’t one because they’re both moving AGAINST their gradients

• • have glucose in your intestinal lumen
• - because of the size of the lumen in comparison to the size of an intestinal epithelial cell, no matter how many candy bars you eat, there will always be ↓ glucose in the intestine than in the epithelial cell (volume issue)

• Na⁺/Glucose Symporter: moves glucose ↑ it’s gradient while moving Na⁺ ↓ its gradient

• once in the cell, Glucose can be transported out into blood using Glucose Permease (carrier protein, passive transport)

• to reestablish Na⁺ gradient, use Na⁺/K⁺ ATPase Pump: actively transports Na+ out into blood & brings 2 K⁺ into cell

• 1. Cystic Fibrosis: defective CF Transmembrane Regulator
• - without a normal CFTR, Cl- transport across the cell membrane is messed up

• 2. Drug Resistance: over-expression of P-glycoprotein/MDR complex (mutant tumors survive because they over-express this ATPase pump that expels chemo drugs from tumor cell)
• MDR PICTURE

3. Tangier Disease

(Hypoglycemia in infancy: Sulfonylurea Receptor)

• rare genetic disorder characterized by severe HDL deficiency in plasma caused by a mutated ATP-Binding Cassette 1 gene (an ATPase that’s important for the efflux of cholesterol from the cell)

• without any cholesterol to pick up, HDL is cleared from the plasma & ends up in various tissues

• hallmark: accumulation of cholesteryl ester (CE) in various tissues leading to severe cardiovascular disease, lymphadenopathy, hepatosplenomegaly & peripheral neuropathy

• ~500 patients world-wide, most on Tangier Island

abnormally LOW HDL

• ↓ HDL → ↑ heart disease

• 1. Phagocytosis
• 2. Receptor-mediated Endocytosis
• 3. Pinocytosis

a receptor-mediated process that internalizes & degrades large objects like bacteria & cell debris (eg. at site of inflammation)

• • bacteria or larger particles (eg. protozoans, asbestos fibers) bind to specific receptors on the cell surface
• • the membrane then Evaginates (outpouches) to engulf the particle, forming a phagosome
• • the phagosome is rapidly acidified by an H⁺/ATPase in the vesicle membrane
• • the phagosome fuses with a primary lysosome to become a phagolysosome
• • lysosomal enzymes are usually able to degrade contents of the lysosome

ACTIN (microfilament)

binding activates receptors that trigger actin assembly

• Legionnaire?s Disease
• Leishmaniasis
• Listeriosis
• Leprosy

• Toxoplasmosis (Coccidiosis)
• Tuberculosis

Streptococcus

4Ls 2Ts 1S

(also inert particles like asbestos or silica fibers pose particular problems because cells can’t degrade by phagocytosis leads to → mesothelioma, black lung)

• bacteria & larger particles → Phagocytosis

• viruses, smaller particles (proteins, macromolecular complexes) → RME

an extrinsic or peripheral membrane protein that helps concentrate ligand-receptor complexes & aids in membrane fission

this protein linked to membrane via other proteins called adaptins

• • proteins or viral particles bind to specific receptors on the cell surface, often in membrane regions coated with clathrin
• • the membrane invaginates & dynamin pinches off the small vesicle (endosome) from the membrane
• • vesicles lose their clathrin coat & then quickly become acidified by an H⁺/ATPase in the membrane
• • the decreased pH facilities its fusion with the CURL (Compartment for Uncoupling of Receptor & Ligand) endosome
• - in the CURL endosome the ligand separates from its receptor & is sorted into separate parts of the vesicle
• • the receptor-containing portion of the CURL buds off & is recycled to the PM to await more ligand
• • ligand-containing part of the CURL fuses with a primary lysosome & is degraded by lysosomal enzymes

• • with LDL/cholesterol, vesicle acidification causes separation of the LDL receptor & cholesterol ligand → cholesterol is degraded by lysosome & LDL receptor is recycled back to the PM
• - in most cases receptor & ligand are designed to stay together at neutral pHs

• • with the transport of maternal antibody, IgG enters baby first in digestive system (intestinal lumen → low pH)
• - F_c receptor binds to IgG ligand in intestinal lumen
• - complex is designed to be stable at LOW pH
• • F_c receptor+IgG is internalized into cell via classic RME
• • acidic early endosome doesn’t disassociate the complex
• • vesicle will transcytose to the extracellular side of the cell, where the pH of neutral blood causes IgG to separate from receptor
• • F_c receptor is recycled via small transport vesicle back to the intestinal lumen side of the cell

• caused by defective receptor-mediated endocytosis that results in the inability of cells to transport cholesterol & results in elevated blood cholesterol & eventually arteriosclerosis

• rare autosomal dominant disease in which homozygotes have extremely elevated cholesterol levels & generally die of cardiovascular problems before the end of their 2nd decade

• • Familial Hypercholesterolemia is caused by some defect in the LDL receptor mechanism & undermines RME
• - revealed the mechanism of cholesterol transport INTO cells
• - because cholesterol can’t get into cells, it builds up in the blood & eventually insudates (soaks into) artery walls, where it exacerbates atherosclerotic lesions
• - death in 2nd or 3rd decade of life when homozygous

• • Tangier’s is caused by a defect in an ABC ATPase that pumps cholesterol OUT of cells
• - revealed the mechanism of cholesterol transport OUT of cells
• - cholesterol builds up & damages endothelial cells that line the large arteries
• - death in the 4th or 5th decade of life
• - there are abnormally low HDL levels in blood because there is no cholesterol in blood

• Influenza Virus
• Rabies Virus

• viruses get into the cell via normal RME but before they can be degraded by lysosome, they fuse their capsid membrane with an endosome & release viral particles into the cell

• the low pH doesn’t kill them in the endosome