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Human Epithelial Biology > Epithelial Ion and Fluid Transport > Flashcards

Epithelial Ion and Fluid Transport Flashcards

1
Q

Why does water movement across epithelia matter

A
  • body temperature regulation
  • mucus movement (pathogen clearance from lung)
  • renal fluid balance
  • digestion and nutrient absorption
  • reproduction
  • diarrhoea (pathogen clearance from gut)
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2
Q

Daily oral fluid input

A

2L

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3
Q

Daily saliva fluid input

A

1.5L

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4
Q

Daily gastric juice fluid input

A

2.5L

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5
Q

Daily bile fluid input

A

0.5L

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6
Q

Daily pancreatic fluid input

A

1.5L

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7
Q

Daily intestinal fluid input

A

1L

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8
Q

Daily total fluid input

A

9L

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9
Q

How much fluid is lost in faeces

A

0.1L

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10
Q

How much fluid is recovered by the small intestine

A

7L

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11
Q

How much fluid is recovered by the large intestine

A

1.9L

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12
Q

Action of cholera

A
  • inhibits fluid reabsorption in gut
  • epithelial function was measured by checking how much fluid was in bucket
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13
Q

The transepithelial potential

A
  • arises from ion movements
  • ionic valency (z), concentration gradient (deltaCion), and ionic permeability (ease at which ion crosses membrane, Pion)
  • ion movements are determined by fick’s law of diffusion
  • to describe flux (J) over cell membrane, other terms are needed (Gion and Eion)
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14
Q

Fick’s Law of Diffusion

A

Movement of flux (Jion) (moles.sec-1.cm-2) = Pion - deltaCion

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15
Q

Problem with ficks law of diffusion

A

Pion is the product of the ion species and concentration gradient, and electrostatic attraction

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16
Q

What is Gion

A

the ionic conductance of the ion across the membrane (amperes) -> measure of ionic movement

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17
Q

What is Eion

A

the electrostatic diffusion potential (volts) -> measure of the size and direction of attracting forces

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18
Q

Transepithelial potential of potassium

A
  • as K+ ions leave cell across chemical gradient, deltaCK diminishes
  • diffusion potential (EK) increases to retain K+ in the cell
  • inward/outward movement of K+ depends on the membrane permeability of K+ (PK, determined by number of pumps/channels/transporters) and is measured by movement of charge (GK)
  • when EK.EK = PK.deltaCK, net flux of K+ = 0
  • value of transepithelial membrane potential (Em) at which equilibrium is established is given by Nernst equation
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19
Q

Nernst Equation

A
  • membrane potential at which equilibrium is established for a given ion
  • Em = RT/zF ln(K[K+]o/[K+]i)
  • Eion = 61log10([ion]o/[ion]i)
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20
Q

Value at which there is no net flux of K+ ions at 37 degrees Celcius

A

Em = 61.log10([5]/[155]) Volts
Em = -0.092 Volts
Em = -92mV

21
Q

The Gibbs-Donnan Equilibrium

A

describes the effect of a non-permeable anion on transmembrane ion difference which drives water transport through osmosis

22
Q

How does water move across an epithelial membrane

A

2 routes:
- intracellular: movement of water occurs within cells and is regulated by water channels known as aquaporins
- paracellular: movement of water occurs between cells and is regulated by tight junction permeability

23
Q

What do we need for water movement across epithelial membrane

A
  • osmotic gradient
  • opening and closing of tight junctions
  • aquaporins (channels specialised for the movement of water)
24
Q

Mechanism of fluid secretion

A
  • presence of a sodium and potassium pump causes sodium to drive inward fluid uptake
  • chloride is moved against gradient and accumulates inside the cell (membrane potential hyperpolarises)
  • adding a chloride channel (CLCN) allows chloride to exit the epithelial monolayer and enter the apical membrane
25
Q

Mechanism of fluid absorption

A
  • opening of tight junctions createsan inward current
  • sodium coupled glucose uptake helps to retain fluid in cases of diarrhoea
  • epithelial sodium channel (ENaC) draws fluid across apical membrane and moves it towards the blood
26
Q

Role of chloride in fluid secretion

A
  • if ENaC dominates all epithelial membranes would dry and therefore we need secretion to go in the other direction using chloride
  • chloride in blood plasma has negative charge so must be coupled with strong electrochemical movement of sodium and potassium to cotransport it across the basolateral membrane
27
Q

Characteristics of Cl- channels epithelial cells

A

fluid secretion (basolateral -> apical transport)

28
Q

Characteristics of Na+ channels epithelial cells

A

fluid absorption (apical -> basolateral transport)

29
Q

Swelling-activated Cl- channel (IClvol)

A
  • activated transiently by osmotic shock
  • sustained opening does not occur
30
Q

Calcium-activated Cl- channel (CaCC)

A
  • activated by release of intracellular Ca2+ stores
  • activity is transient
  • unlikely to be sustained in development
31
Q

Outwardly Rectifying Cl- Channel (ORCC)

A
  • regulated by release of intracellular ATP
  • maintains cell membrane potential by regulated depolarisation to physiological set point
32
Q

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

A
  • best characterised channel due to role in CF
  • long presumed to be channel regulating fluid secretion in adult lung
33
Q

Voltage-dependent Cl- channels (CLCN)

A
  • recently characterised in lung
  • expression pattern follows process of lung development
34
Q

The CFTR

A
  • member of ATP binding cassette glycoprotein superfamily
  • 170kDa glycoprotein Cl- channel composed of 2 6-span transmembrane domains (pore), 2 nucleotide binding domains (NBD1 and 2), and a single R domain of highly charged AAs
35
Q

The R domain of the CFTR

A
  • a regulatory site containing several phosphorylation sites for protein kinases A and C
  • activation of CFTR Cl- conductance requires ATP binding to the NBD domains and phosphorylation of the R domain
36
Q

Role of NBD1 and NBD2 in CFTR

A
  • hydrolyse ATP
  • provides kinetic energy to open channel
37
Q

Normal cycle regulation of CFTR

A

1) channel is inactive
2) cAMP activation of PKA phosphorylates R domain
3) ATP binds to NBD1&2
4) ATP is hydrolysed
5) channel opens and conducts Cl-
6) dephosphorylation of the R domain inactivates the channel

38
Q

Loss of Phenylalanine 508 in NBD1 region of CTFR

A
  • causes CF
  • causes CFTR to be misfolded and sticks in ER, where it is broken down and never reaches membrane
  • results in no fluid in airway secretion (dry lung), sticky mucus and pathogen colonisation
  • treatment for CF reinstates the appropriate folding and translocates it back to membrane
  • gene therapy treatments
39
Q

Voltage-dependent Cl- ion channels (CLCN 1…7)

A
  • widely distributed (found in epithelia, muscle, nerve tissue, also plants)
  • channel opening is “gated” by membrane potential
  • CLCN2 expressed in the epithelium is activated at negative (hyperpolarised) cell membrane potentials
  • CLCN2 and CLCN3 are developmentally expressed in the foetal lung and control lung fluid volume during development
40
Q

Structure of voltage-dependent Cl- ion channels (CLCN 1…7)

A
  • 10 transmembrane domains which dimerise to form two pores
  • each pore is voltage gated
41
Q

Mutations in voltage-dependent Cl- ion channels

A
  • CLCN1 mutation: myotronia (failure of muscles to relax after contraction -> cells remain depolarised)
  • CLCN5 mutation: Dent’s disease (fluid transport problems in the kidney resulting in kidney stones, calcium and protein loss in urine)
42
Q

The ENaC channel

A
  • found in all secretory epithelia
  • composed of 3 subunits (alpha, beta, gamma)
  • genetic knockout of alpha is lethal at birth due to flooding of lungs
  • knockout of beta or gamma is not lethal but associated with reduction in rate of Na+ transport
  • alphaENaC is the dominant pore-forming subunit
  • association with beta and/or gamma is required to form a tetramer and confer Na+ selectivity
43
Q

Structural domains of ENaC subunits

A
  • cysteine-rich region on extracellular loop (rich in CSSC sulphur cross linking -> determines tertiary structure
  • histidine glycine residue rich region involved in channel opening and closing
  • proline tyrosine residue rich region which serves as a binding motif for NEDD4 (ubiquitin ligase which targets the subunit for membrane removal and proteolytic degradation)
44
Q

Inhibition of ENaC

A
  • Amiloride
  • selective Na+ channel blockage shows high potency for ENaC blockers (benzamil and amiloride)
45
Q

Activation of ENaC

A
  • beta2 Adrenergic agonists (e.g. Isoproterenol)
  • conductance is induced by catecholamines
46
Q

Pseudohypoaldoseteronism (PHA)

A
  • hereditary
  • associated with resistance to aldosterone, leading to increased sodium excretion, dehydration, hypotension, hyperkalaemia, and metabolic acidosis
  • disease is most evidence in kidney, sweat gland, pancreatic and salivary gland function
  • can be lethal due to excessive hypotension and circulatory collpase
  • results in excessive fluid retention in lung airways due to sustained Cl- secretion and inability to absorb Na+
  • most lethal form caused by loss-of-function mutations in alpha, beta and gamma ENaC
47
Q

PHA effect in renal system

A
  • high Na/2Cl/K uptake
  • high basolateral K+ secretion
  • membrane removal and degradation
  • Na+ secretion in urine
  • ENaC channel recognized for degradation by NEDD4
48
Q

Liddle’s Syndrome

A
  • hereditary
  • characterised by salt-sensitive hypertension, hypokalaemia, metabolic alkalosis, and repressed aldosterone secretion
  • results from gain-of-function mutations in C-terminal domain of beta or gamma ENaC which results in deletion of 45-75 amino acids from proline-tyrosine rich PY domain
  • WT PY motif binds to NEDD4 (ubiquitin ligase) promoting internalisation and degradation of subunit
  • loss of repressor activity = sustained Na+ absorption
49
Q

Hypernatraemic effects of Liddle’s Syndrome in Renal System

A
  • ENac accumulation at apical membrane
  • degradation of NEDD4 = sustained Na+ absorption
  • increased Na+ pump activity compensates for Na+ uptake and causes Na+ secretion into blood with no route for removal

Human Epithelial Biology (7 decks)

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