Transcript Zool 352 Lecture 14 - Washington State University

Nutrient Transport
Balance Between Absorptive and
Secretory Processes in Gut
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Figures for adult human
Secretion
• Absorption
1500 ml saliva
• 8500 ml sm. Intestine
2000 ml gastric
• 400 ml colon
secretion
• Total: 8.9 liters/day
500 ml bile
1500 ml pancreatic
juice
1500 ml intestine
Total: 7 liters/day
New cells (crypt cells) primarily indulge
in secretion; older cells transform into
mainly absorptive cells (villous cells.)
Intestinal
epithelial ells
(enterocytes)
are generated
from stem
cells at the
bases of the
villi. As they
age, they
ascend the
villi, dying
shortly after
they reach the
tips.
Transporters in Absorptive
Enterocytes (villous cells)
• Apical Processes
• Na+ gradient-coupled
cotransporters for
sugar and amino acid
• Na+/H+ exchanger
• Cl-/HCO3- exchanger
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Basolateral Processes
Na+/K+ ATPase
Cl- channels
K+ channels
Generalized picture for absorptive cells
in the small intestine
Important features of the transcellular path
for solutes in small intestine
• Processes driven by Na+ gradient: Sugar and
amino acid absorption
• Processes driven by metabolic CO2
production: Cl- absorption, Na+ absorption
• As a result of these coupled processes,
Na+/Cl- entry is electroneutral, unlike the
frog skin
• As in the frog skin, the Na+/K+ pump is the
only primary active process.
Electrical properties of the small
intestinal epithelium
• 1. “Tight” junctions are quite leaky, so
tissue electrical resistance low
• 2. Coupled, electroneutral apical processes
result in small transapical voltage
• As a result, intestinal transepithelial
potentials are small - of order of 5-15 mV.
Fluid transport by leaky epithelia
• Water follows solute movement (always!)
• The intestine is so leaky to water that a
large osmotic gradient is not needed to drive
water absorption - an almost immeasureable
1-2 mOsM difference may be sufficient.
• The extreme leakiness of the epithelium to
water is probably due in part to the presence
of water channels, giving water a
transcellular as well as a paracellular path.
lack of the Cl-/HCO3- exchanger congenital chloride diarrhea
• Cl- fails to be absorbed and HCO3- doesn’t
get secreted
• Consequences:
– net Cl- loss in feces
– water reabsorption impaired - diarrhea
– Na+/H+exchanger still operates, so net loss of
H+ and retention of HCO3- causes alkalosis.
Intestinal secretion
The transbasal carrier is
the Na+, K+, 2Cl
cotransporter (NKCC)the driving force for the
NKCC is provided by the
Na+ gradient. The
“electrogenic” transapical
Cl- movement is by way
of Cl- channels. Cl- can go
downhill through the
channels because of the
basal NKCC.
Cholera- a toxin interferes with
regulation of the apical Cl- channels
• Open probability of apical Cl- channel is
increased by cyclic adenosine
monophosphate (cAMP) – ordinarily, this is
an effect of activating the beta adrenergic
receptors of the intestine.
• Cholera toxin ribosylates the alpha subunit
of Gs, converting it into a permanent
stimulant of adenylyl cyclase.
Cholera toxin causes secretory
diarrhea
• In presence of excess cAMP, Cl- channels
stay open much of the time, so secretion
overwhelms absorption.
• Result: a secretory diarrhea, with loss of
extracellular fluid volume = hypovolemia
or dehydration.
Apical Cl- channels are involved in
secretion in a number of epithelial
tissues
Salivary, tear and sweat gland
Respiratory airway
Pancreas
Kidney – the disease gets its name from its
effects on renal anatomy
Cystic fibrosis is the result of mutations
of a common apical Cl- channel, CFTR
CFTR= “cystic fibrosis transmembrane conductance
regulator”
Mutations reveal the function of different
parts of the CFTR
• Mutation at NBD1 interferes with targeting
to the plasma membrane
• Mutations in TM1 and TM6 reduce channel
conductance
• Mutations in the regulatory domain (R)
make the channel insensitive to regulatory
signals that would turn it on. Ordinarily,
phosphorylation of R activates the channel.
The upper traces at the
left show the activity
of the CFTR channel
from shark
epithelium.
The open circles in the
V/I plot are for the
shark channels; the
closed ones are for the
human channel.
CFTR
Some reabsorptive
epithelia reverse
the picture for
secretory epithelia
The cartoon of the
thick ascending
limb of the loop of
Henle in the
kidney shows
NKCC on the
apical membrane
and CFTR on the
basolateral
membrane. The
presence of CFTR
in this tissue
explains why CF
patients have renal
symptoms.
At the end of this lecture you should be able to:
Summarize the mechanisms typically involved in salt
reabsorption in “tight” epithelia like the frog skin and
in “leaky” epithelia like the intestine.
Contrast the mechanisms typically involved in
reabsorptive epithelia with those involved in secretory
epithelia.
Explain the underlying cellular basis of cholera
diarrhea and cystic fibrosis.
Explain the basis for inclusion of glucose and Na+ in
rehydration solutions.