2. Introduction
The aquaporins (AQPs) are a family of
small membrane-spanning proteins
(monomer size ∼30 kDa) that are expressed
at plasma membranes in many cells types
involved in fluid transport.
3. Structure
Basic features of aquaporin structure have
been defined using mutagenesis, epitope
tagging, and spectroscopic and freeze-
fracture electron microscopy methods.
Aquaporins appear to assemble in
membranes as homotetramers in which
each monomer, consisting of six
membrane-spanning α-helical domains
with cytoplasmically oriented amino and
carboxy termini.
4.
5. NPA DOMAIN
The two highly conserved NPA motifs are the
most important structural domains that play a
crucial role in water-selective permeation in
aquaporin water channels.
Orientation of the water molecules moving
through the channel assures that only water
passes between cells, due to the formation of a
single line of water molecules.
6. AR/R SELECTIVITY
FILTER
The ar/R (aromatic/arginine)
selectivity filter is a cluster of
amino acids that help bind to water
molecules and exclude other
molecules that may try to enter the
pore. It is the mechanism by which
the aquaporin is able to selectively
bind water molecules (hence
allowing them through) and
prevent other molecules from
entering.
7. Functions of aquaporin
Aquaporins are "the plumbing system for cells," .
Aquaporins selectively conduct water molecules in and out of the cell,
while preventing the passage of ions and other solutes. Also known
as water channels, aquaporins are integral membrane pore proteins.
However, the water pores are completely impermeable to charged
species, such as protons, a property critical for the conservation of the
membrane's electrochemical potential.
Water molecules traverse through the pore of the channel in single file.
The presence of water channels increases membrane permeability to
water.
One type of cell in which aquaporins are found is in the epithelium of
the human kidney, in the distal and collecting tubules. The antidiuretic
hormone (ADH) stimulates epithelial cells to incorporate aquaporins
into their membranes, increasing the uptake of water from the tubule
into the cells, and therefore increasing the reabsorption of water into
the body.
8. The gating of aquaporins is necessary to keep
cells hydrated during periods of drought. The
mechanism in some aquaporins involves the
dephosphorylation of certain serine residues,
causing the protein to change shape. This change
in shape causes the tunnel of the protein to close
and not allow any water to pass through.
In oocytes it transport glycerol and to some
extent urea, along with water.
9. AQUAPORINS AS TARGETS FOR
DRUG DISCOVERY
AQPs mediate water movement into the antral
follicle and play important roles in follicle
development.
AQPs are known to be involved in the early
stage of spermatogenesis, in the secretion of
tubule liquid and in the concentration and
storage of spermatozoa.
AQPs take part in the processes of fertilization,
blastocyst formation (as the pathway for
transtrophoectodermal water movement during
cavitation) and implantation.
10. Importance of Aquaporins
Aquaporins are known to play a big role in
various aspects of normal body function.
Many mammalian AQPs, including AQP1, AQP2,
AQP4, AQP5 and AQP8, function primarily as
bidirectional water-selective transporters.
It is seen that most, if not all, significant
biological functions of the mammalian AQPs,
can be attributed to AQP facilitated water and/or
glycerol transport.
11.
12. AQPs in epithelial fluid transport
A major role of epithelial cells is the transport of
fluid across tissue barriers. Certain epithelia
carry out what has been called ‘active near-
isosmolar’ fluid transport, such as fluid
absorption by kidney proximal tubule and fluid
secretion by salivary gland acinar epithelium.
Active trans-epithelial fluid transport involves
the generation of an osmotic gradient by active
solute transport, which drives osmotic water
transport. The high trans-epithelial water
permeability conferred by AQPs, increases net
fluid transport.
13. Aquaporins in the Brain
AQP4 is thought to be involved in brain swelling. But it
is the astrocytes rather than epithelial cells that are
involved.
AQP4 is also involved in neural signalling. AQPs are
expressed in electrically excitable tissues in supportive
cells adjacent to excitable cells. that AQP4-dependent
water permeability enhances K+ transport by a ‘pseudo-
solvent drag’ mechanism. Neuro-excitation involves ion
buffering in the ECS, which is the small aqueous
volume surrounding cells. Excess K+ released by
neurons during excitation is taken up and ‘siphoned’
largely by astrocytes. It is postulated that AQP4-
facilitated water transport in astrocytes in the brain is an
important determinant of both water and ion movement
between cells and the ECS during neuroexcitation.
14. Other Uses of Aquaporins
Certain types of AQPs are involved in cell
migration. AQP-facilitated cell migration appears to
be a general phenomenon relevant in angiogenesis,
tumour spread, wound healing and immune cell
chemotaxis.
Recent studies have indicated roles for aquaporins
in skin hydration. The channels involved in this
process are AQP3 and AQP7.
AQP3 is also involved in cell proliferation.
AQP7 is found to be involved in fat metabolism.
15. Aquaporinopathies
Aquaporinopathies are human aquaporin diseases
cased by mutations in aquaporin structure. These
diseases are extremely rare.
One of the most common aquaporinopathy is the
one caused by mutations in AQP2 which cause
non-X-linked Nephrogenic Diabetes Insipidus
(NDI). The incidence of NDI caused by AQP2
mutations is fewer than one in 20 million births.
Mutations in AQP0 in lens fiber cause congenital
cataracts by a mechanism that is speculated to
involve defective cell–cell adhesion rather than
impaired water transport.
16. Aquaporin and it’s correlation to
obesity
Recent studies indicate that Aquaporins play a
major role in the incidence of obesity.
Aquaporins selectively conduct water
molecules in and out of the cell, while
preventing the passage of ions and other
solutes, also known as water channels.
But some of AQP, known as
aquaglyceroporins, also transport other small
uncharged solutes, such as glycerol, CO2,
ammonia and urea across the membrane,
depending on the size of the pore.
17. A subset of the AQPs, the aquaglyceroporins
AQP3, AQP7 and AQP9, transport both water
and glycerol.
AQP7 is expressed in the plasma membrane of
adipocytes.
Aquaglyceroporins, have a less-constricted
pore compared with that of water-selective
AQPs (diameter of 3.4 Å compared with 2.8 Å,
respectively)
Also have relatively more hydrophobic residues
lining the pore.
AQP9 has been suggested as an important
route for hepatic glycerol uptake.
18. AQP7- null mice manifest
adiposity hypertrophy
reduced plasma membrane glycerol
permeability
cellular glycerol and triacylglycerol
accumulation, and glycerol kinase up
regulation
19. Recent Studies
Since its discovery Aquaporin has been found to
involved in various physiological functions
In mammals Aquaporin has been shown to play an
important role in urine production and water
regulation .
Many disorders that are caused due to defective
functioning or deficiency /absence of Aquaporin .
Many therapies that target Aquaporin have been
developed
Likewise many diagnostic techniques that are based
on Aquaporin have been developed
20. Clinical Significance
The primary cause of nephrogenic diabetes insipidus
( a condition characterized by excretion of large
amounts of dilute urine) has been found to mutations
occurring in the Aquaporin – 2 gene
Congenital cataracts in mice are caused due to
mutations in Aquaporin 0 gene
Autoimmune reactions caused by Aquaporin 4
causes Devic’s disease ( an autoimmune disorder
where the body’s own immune system attacks optical
nerves and the spinal cord )
21. Therapeutics
The discoverers of Aquaporin, Peter Agre et al suggested that
if aquaporins could be manipulated, medical problems such
as fluid retention in heart disease and brain edema after
stroke could be solved
Compounds like tetraethylammonium, acetazolamide and
arylsulfonamides have been found to inhibit the action of
Aquaporin . These compounds are undergoing clinical trials
Aquaporin can be inhibited by heavy metals like gold and
mercury but these metals are highly toxic
AQP inhibitors can be useful in diuretic edamatous states that
occurs after ischemic stroke and spinal cord injury and
reduce brain swelling that occur in diseases like encephalitis
and meningitis
22. Diagnostics
Aquaporin 4 causes an immune disorder called
Devic’s disease. Antibodies specific for APQ 4 are
found in patients with this disease. These
antibodies can be used for accurate diagnosis of
Devic’s disease
These antibodies can also be used for diagnosing
diabetes insipidus . AQP’s have been found to be
excreted in urine . A person suffering from diabetes
insipidus will have very low amount of functional
AQP’s in the urine .Hence a rapid diagnosis of this
disorder is possible using this technique
These diagnostic techniques have been performed
at the experimental level . More research has to
done to prove the effectiveness of this technique .
23. References
A. S. Verkman, “Aquaporins at a glance”, doi:
January 14, 2011. J Cell Science, 2107-2112.
Chou, C. L., Knepper, M. A., Hoek, A. N., Brown, D.,
Yang, B., Ma, T. and Verkman, A. S. (1999). Reduced
water permeability and altered ultrastructure in thin
descending limb of Henle in aquaporin-1 null mice. J.
Clin. Invest. 103,491 -496.
A. S. Verkman, “Aquaporins: translating bench
research to human disease” ,
doi: 10.1242/jeb.024125June 1, 2009 J Exp
Biol 212, 1707-1715.
Notes de l'éditeur
Title can be changed as per give by the teacher
Title can be changed as per give by the teacher
Adipose hypertrophy or adipose tissue hypertrophy change as per convenience