lecture 17/18 Flashcards
CFTR activation pathway
-Cystic Fibrosis Transport conductance Regulator
-GPCR/G protein/adenylyl cyclase/cAMP/Protein kinase phosphorylates R domain/ATP binds to Nucleotide Binding Domain/hydrolysis energy opens channel
Oral rehydration therapy
-Sodium Chloride and glucose to stimulate water uptake into cells
-pump of sodium across membrane attracts Cl- and H2O through paracellular transport so isotonic fluid movement
-used to treat secretory diarrhea (cholera) but not osmolarity induced diarrhea
Cystic fibrosis lung pathology
-CFTR gene mutation so disfunction or missing
- Cl- can’t move out of cell.
-Hypotonic, water moves into cell
-dry surface, thick sticky mucus, cant breathe
kidneys tight junctions effect
tight junctions tighter/more selective at distal end to reabsorb NaCl (more transcellular transport)
tight junctions less strands/more permeable at proximal end to reabsorb most filtrate -bulk movement water/glucose (more paracellular transport)
facilitated diffusion
-carrier or channel transport protein
-no atp
-solute moves down conc. gradient
treatment for glucose/galactose malabsorption
-glucose can’t pass through SGLT protein
-fructose diet replaces glucose
-fructose can diffuse across apical membrane of cell via GLUT 5, diffuse across basal-lateral membrane via GLUT 2
diabetes glucosuria
-plasma glucose levels above renal threshold 200 mg/100mL
-maximum glucose transport on left y axis = 375 mg/min
-right y axis amount of glucose in urine
-SGLT saturation so glucose not absorbed and found in urine
secretion
entry: basal-lateral membrane has Na/K pump establish gradient, glucose diffuse into cell from blood with Na
exit: apical membrane, glucose diffuse out, may need active transport to enter another cell
absorption
entry: apical membrane has Na/K pump establish gradient, has glucose/Na symporter bringing glucose into cell
exit: basal-lateral membrane, glucose diffuses out
GIT/kidneys proximal
-duodenum in the small intestine
-proximal tubule in the kidneys
-lots of paracellular transport
-90% of transport
GIT/kidneys distal
-colon in GIT
-collecting duct in kidneys
-lots of transcellular transport
-10% of transport
cystic fibrosis vs cholera in chloride secretion
cystic fibrosis: cystic fibrosis transport conductance regulator (CFTR) disfunction so Cl- can’t move out of cell (lung surface dehydrates)
cholera: enterotoxin skips receptor, irreversibly binds to adenylyl cyclase so CFTR effectively always open. Cl- out of cell attracts Na+ and H2O so excessive fluid loss from cells.
sweat formation secretory coil pathways
parasympathetic (rest, digest) - acetylcholine activates IP3, Ca2+ path. Ca2+ binds to calcium gated chloride channel
sympathetic (fight/flight) - noradrenaline activates cAMP production/ kinase A phosphorylates R domain of chloride channel
both isotonic fluid secretion
why does Cl- move into cell in reabsorptive duct of sweat formation
membrane is depolarised from -80 to -60 millivolts so Cl- can move down conc. gradient
cystic fibrosis sweat formation
-CFTR mutated/broken so no sweat forms by sympathetic pathway, only via parasympathetic calcium gated chloride channel
-no reabsorption as only CFTR in this duct so salty sweat
signs of cystic fibrosis
-super salty sweat
-defects of epithelia cells
organs affected by cystic fibrosis
pancreas, liver, GIT, airways, reproductive tract, skin
obstruction by cystic fibrosis affects which organs?
Pancreas - enzymes can’t be delivered for digestion
Airways - clogging of bronchioles impedes breathing, most CF patients die from lung disease
Liver - blocking of bile ducts impedes digestion, can prevent liver function
Female reproductive - occasionally mucus plug blocks sperm from uterus
Small intestine/large intestine - colon blocked
glucose/galactose malabsorption cause
sodium-glucose linked transporter mutation prevents glucose from entering cell –> higher osmolarity in small intestine lumen –> excessive water diffusion into lumen causing diarrhea
chloride secretion mechanism
gradient set up by:
1.) primary active transport - 3Na+/2K+ pump
2.) 2Cl-/Na+/K+ symporter so high conc of Cl- in cell
3.) Cl- can only leave cell if CFTR activated, Na+ leaves cell either via pump or channel
4.) movement of Cl- induces water and Na+ movement into lumen
secretory diarrhea mechanism
overstimulation of CFTR either by secretagogues from inflammation or tumours (reversible binding) or more commonly cholera enderotoxins (irreversible)
secretory diarrhea location of oversecretion
in crypt cells of small intestine or colon
secretion overwhelms the absorptive capacity of colon causing secretory diarrhea
cystic fibrosis overview
autosomal (affecting any non sex 22 chromosomes) recessive disorder
heterozygotes have no symptoms but there are carriers
affects children and young adults (older die median age survival 38)
