Aquaporin 1 In Mammalian Cells Biology Essay


Aquaporins belong to the family of major intrinsic proteins and are most commonly referred to as water channels. These aquaporins are widely distributed in organs and tissues of mammals and are mainly responsible in transporting water. The present review gives an overview of the structure, mechanism of water selectivity and the function of AQP1 in mammalian organs and tissues. Emphasis will be given out on the structure of the AQP1 which helps the AQPs to behave multifunctional and highly adaptive than simple water pores.


Water plays an important role in all organisms ranging from unicellular to multi-cellular. The molecular mechanism of water absorption and releasing by the major barrier, plasma membrane remained unknown until the discovery of transport proteins was obtained. However, it was seen that additional water selective pores were necessary in order to explain the high water permeability in certain cells such as red blood cells and the renal tubules. The existence of the molecular channels which were responsible for the high permeability was confirmed in 1987 through the discovery of 28kDa integral membrane proteins that were present in these cells(tubules) which was initially known as CHIP28 and later renamed as aquaporins(R).

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At present 13 aquaporin forms have been identified in mammals(J110,14,26). The classification of these aquaporins include three groups as follows 1) Classical aquaporins which are selective to water (AQP1, AQP2,AQP4,AQP5) 2) Aquaglyceroporins that are permeable to small solutes such as urea and glycerol ( AQP3, AQP7, AQP9, AQP10) and 3) unorthodox aquaporins of which the function still remains unknown(AQP6, AQP8, AQP 11 and AQP12)(J1).

In this review the main focus will be driven towards the structure, water selectivity and the diverse function of the AQP1 membrane channels in mammals which participates in a varied number of physiological processes when compared to the simple water pores.

Architecture of mammalian aquaporin 1

The aquaporin functional unit is known to be a tetramer. Each monomer present in the tetramer acts as an independent water pore. When the monomer is viewed to the plane of membrane it shows to contain six transmembrane helices bound together which form a part of a trapezoid like structure.

Six putative helical domains are suggested to be found in aquaporins which were determined by hydrapathy profiles. Studies involving epitope tagging, aquaporin reporter chimeric studies and site specific mutagenesis studies have shown that the -NH2 and -COOH terminal ends are projected towards the cytoplasmic region. The membrane helices are arranged such as follows(Figure1). In most type of aquaporins contain the consensus sequence of N-linked glycosylation sequence which are generally monoglycosylated in native tissues. However, this feature does not show an importance in the function of the aquaporins. Even though there are six membrane spanning motifs thought to be present in all type of aquaporins, only the AQP1, AQP2, AQP4 have been experimentally proven to have the presence of these motifs.

Figure 1-

Six membrane spanning helical domains with amino and carboxyl regions termini s facing the cytoplasmic region.

Pore structure

The AQP1 pore is a dumbbell like structure which contains three main regions known as extracellular vestibule, extended narrow pore or selectivity filter (containing the constriction region) and a cytoplasmic vestibule. The selective channel contains both hydrophobic and hydrophilic residues in an equal ratio. The hydrophilic face possesses certain chemical groups that are responsible in the transport of water.

A conical shape vestibule mouth of 15° A in diameters is observed due to the N- and C-terminal residues present in the cytoplasmic face and the loop regions of the monomer face. The surface of the extracellular vestibule consist a small number of polar charged groups and polar groups of solvent exposed backbone of extended loop regions.

A diameter of approximately 2.8 ° A is observed at the constriction region which is located after a 20°A distance of the extracellular vestibule followed by the 20°A long selectivity region. The key element of the selectivity filter, the helix linker is formed by the residues G190, C191, G192 and I193 of the connecting loop that leads to the non-transmembrane helix M7 (Fig 3 ).

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Figure 2-

The AQP1 amino acid sequence of bovine serum and human aligned using CLUSTAL W5. The AQP1 helixes are shown ad M1-M8.

In the constriction region the hydrophilic region is formed by the H182 in which the azole group orients towards the pore and the R197 residues pointed upwards, parallel to the pore axis and the solvent accessible carbonyl oxygen of residue C191 ( Figure 4). The hydrophobic region is found opposite the hydrophilic region defined by the F58 residue.

Figure 3-

The water molecules that are present in the selectivity filter which forms the hydrophilic force.

The residues R197, H182 and F58 present in the constriction region are conserved across water specific aquaporins(20). These amino acids provide a strong evidence for the specificity of water in the aquaporins.

Figure 4

Residues present in the constriction region

An increase in the pore diameter to 4°A is observed after passing the constriction region which extends to an approximate distance of 15 °A. After an 8°A distance from the constriction point residues in the highly conserved NPA (Arginie, proline, alanine) regions are brought in close proximity due to the end to end packing of the M3 and M7 helixes. Thus the N194 and N78 asparagine residues of the NPA motifs are placed within the pore.

The residues C77, H76, A75 and G74 of the connecting M2 and M3 helix provide carbonyl oxygen that lines the pore which extends towards the cytoplasm vestibule instead of the NPA motifs. A large portion of the hydrophilic nature in the selectivity filter is formed by the pore accessible carbonyl oxygen and asparagine amino acid groups that are present in the long pitched helical half.

A pore accessible H76 is present towards the end of the selectivity filter. It is to be seen that in the aquaporin super families the H76 is highly conserved than the H182.

A 15°A wide cytoplasmic vestibule is formed at the last 8-10°A of the channel. The cytoplasmic vestibule is observed to be conical shape due to the uniform height of the wall.

Water transport of AQP1

The measurement of water transport within aquaporins is generally studied using osmotic swelling assays carried out in Xenopus oocytes which contain the aquaporin cRNA. The measurements are carried out quantitatively by deducing the time duration taken for oocytes to swell due to the response taken for the decrease of the osmolabily change from 200 to 0-100 mosmol/kg of water. Biophysical techniques such as stopped flow light scattering, total internal reflection fluorescent microscopy, laser interferometry and Fourier optic dark field phase contrast microscopy have been used for the studies carried out.

Proteoliposomes when reconstituted with AQP1 have shown to increase the water permeability 100 fold when compared to liposomes that were controlled. However there was no increase to be seen in urea and proton permeability. Also AQP1 voltage clamp studies have indicated that there was no ion conductance to be seen. Thus it was concluded that AQPs were able to transport water by excluding other solute particles present. Explanation for the water conductivity has been explained by steiric hindrance. However other factors such as electrostatic interactions, hydrogen bonding are also shown to be responsible for the loss of proton and ion conductance by aquaporins. Water is thought to flow in either direction down its potential gradient through the pore. Water movement through the pore is also thought to occur due to a single exclusion mechanism. Movement of water can be seen in the presence of mercuric chloride, which is thought to be due to the reagent binding to the cysteine residue that is present near the pore. Within an AQP1 water molecules can be observed in four locations(fig3).

The solute selection by an aquaporin is obtained due to the steric limit of ≈ 2.8 ° A at the constriction region and the chemical properties of the residues that are responsible for the formation of the structure. In order for a water molecule to enter the channel it should reduce the diameter of the molecule by removing the waters of hydration. This process to occur in an energetically favourable manner it is necessary that the primary shell water interaction should be replaced by the residues that are present in the surface of the AQP1 channel wall. Since the AQP1 wall contains a high amount of H-bonding residues it is possible for this phenomena to occur easily at the constriction region such as H182, R192 . The carbonyl back bone of residues G190, C191, G192 are also responsible in the removal of the water shells that are present in a water molecule.

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The selectivity filter contains three water molecules even though it is regarded as a hydrophobic region. The water molecules in this region are found to be bound to the hydrophilic nodes that are present within the selectivity region. Thus the energy barrier for the water transport is overcome by the hydrophilic substances. The water transport of the aquaporin is also facilitated due to the amphipathic nature of the selectivity filter.

Function of Aquaporin 1 in mammals

Cellular activity and signalling in a cell are regulated by water movement thus the aquaporins play a major role in cells. The presence of aquaporins in a mammalian organism is quite ubiquitous and are not localised at a specific tissue. However it has been noted that their distribution in specific cell types indicates the specific function due to the increase in the permeability of water. Thus the aquaporins are important in the fluid homeostasis maintenance and secretion/ re-absorption.

The first characterized aquaporin, AQP1 is widely expressed in brain, red blood cells, lungs and kidneys which is important in water re-absorption and secretion of fluid(W199). Recent studies have indicated that the AQP1 is involved in the cerebrospinal fluid secretion(W199).

AQP1 present in kidneys are most prominently expressed in the nephrons which plays an important in the retrieval of water from primary urine(W1). It is present in the apical and baso lateral membrane of the proximal tubules, descending thin limbs of Henle and the outer medullary descending vaso recta. Aquaporin acts as a water selective pore in all these segments. Studies carried out by deleting the AQP1 gene of mice has revealed that the mice resulted in a high level of polyurea. The presence of aquaporins help in creating an osmotic driving force for the re-absorption of water across the duct(R1). The AQP1 has also been demonstrated to be useful in cell migration due to the defective cell migration that was observed in AQP1 null endothelial cell(R1101).

Brain aquaporins are shown to play an important role in the production, circulation and homeostasis of the cerebrospinal fluid (CSF). The CSF is formed by the water and salt that has been secreted by the choroid plexus epithelium. AQP1 is a predominant aqauporin in the brain(A1). It is also shown to be present in the apical pole of the choroid plexus epithelium cells. The sodium ion passage is through the central pore that is present in the tetramer of the AQP1 through pharmacological studies and protein modelling tools and that it involves a gating mechanism which is regulated by cGMP. However studies are yet to be carried out relating to the functionality which seems to be tissue specific(W52,140,142,143). This has a possibility of participating in the rate of secretion of CSF.


After the discovery of aquaporins twenty years before, it can be seen that these membrane channels have been cloned and functionally studied due to the relative ease of its purification. However, the intramolecular dynamics of these proteins are yet to be explored. The AQP1 is been currently extensively studied in mammals to study its involvement in Alzheimer's disease. Ongoing research is been done in order to express the AQP genes and study their involvement in pathophysiological processes.