Human Aquaporin-4 Protein

Imani Rucker '23 and Tara Cerny '24

Contents:

I. Introduction

Aquaporin-4 (AQP4) is the primary water transport protein in the mammalian central nervous system (CNS). AQP4 is additionally expressed in epithelial tissues surrounding sensory organs that play a role in auditory, optical, and olfactory discernment. This protein is also crucial for maintaining homeostatic equilibrium in the kidneys and lungs. Absorption and secretion of water and other bodily fluids that are water-heavy are precisely regulated with drugs that target AQP4 being highly sought after.

One Aquaporin-4 monomer is composed of 6 domains and 5 loops that span the lipid bilayer of a cell. 4 monomers then assemble to form one tetramer. This is true for all aquaporins. AQP4 is water-specific, meaning that it does not transport solutes or glycerol like the aquaglyceroporins, but it may aid in the transport of potassium ions during the repolarization stage of a neuronal action potential. AQP4 does not allow for the passage of protons. AQP4 has 2 main structural isoforms in the brain and spinal cord: M1 and M23 which correspond to differently positioned methionines. 

II. General Structure

The AQP4 secondary structure contains 6 and 5 loops that connect them. are full-sized while are half-sized. The amino as well as the carboxy terminal are both located on the cytoplasmic extracellular side of the membrane.

The monomer form of AQP4 can transport water on its own, but 4 monomers arrange themselves into a cube-like tetramer with four known permeable pores. There is a fifth pore that forms in the center whose purpose still remains a mystery to researchers. 

III. Cellular Distribution

Aquaporin-4 is abundantly expressed in glial cells associated with the blood-brain barrier and cerebrospinal fluid modulation. AQP4 is predominantly expressed in a particular type of glial cell, astrocytes, in the end feet region where the glia makes contact with a blood vessel. These satellite cells promote structural integrity, axon guidance, and regulated blood flow.

AQP4 is predictably found in areas where water transport is crucial to the organ-specific function like the olfactory mucosa (smell), the Muller cells of the retina (sight), the basolateral domain of the cochlear duct (hearing), and the salivary glands (taste). Aquaporin-4 is constitutively expressed in the inner medulla of the kidneys. 

IV. Water Transport

Water passes through a narrow channel created by 2.5 of the 24 alpha helices. This 2.8 angstrom houses the conserved asparagine-proline-alanine . These motifs are extremely hydrophobic. This speeds the water through the pore as fast as possible. As a single water molecule enters the pore single-file, the oxygen, which leads the way on entry, flips 180 degrees midway and exits the AQP last. Some have speculated that electrostatic fields from the half-helices B and E cause the flip. Another theory suggests that the polarity of Asp in the NPA motif causes it.

are critical for the mediation of water flow. Phosphorylation at Ser-111 can cause an increase in conductivity of up to 40 percent. Phosphorylation at Ser-180, on the other hand, causes a 50 percent decrease in conductivity. Ser-111 has been hypothesized to interfere with the restrictive hydrogen bonding at the N-terminus and therefore open the gate. 

V. Clinical Significance

Aquaporins in the CNS are often tightly controlling the secretion and absorption of cerebrospinal fluid. The brain, being encapsulated inside the inflexible bones of the skull, is especially hypersensitive to shifts in intracranial pressure. The compression of cerebral tissue (edema) can cause many neurological diseases.

Attempting to inhibit the function of AQP4 in the CNS has come with conflicting results. Ammonium compounds, antiepileptics, and serotonin receptor agonists have been shown to reduce water transport and also to have no effect at all.

phosphorylation is a well-studied mechanism that allows for AQP4 to become more permeable by opening up the channel on the cytoplasmic side of the cell membrane.

Another area of intrigue lies in the autoimmune disease neuromyelitis optica (NMO). The Aquaporin-4 channels are attacked directly, impacting the functionality of the optic nerve and spinal cord. AQP4-specific antibodies (NMO-IgG) activate demyelination of neural axons and necrosis. If the point of attachment (epitope) between AQP4 and NMO-IgG could be blocked or changed, the effects of NMO could be significantly slowed or stopped. 


VI. References

Gleiser, C., Wagner, A., Fallier-Becker, P., Wolburg, H., Hirt, B. and Mack, A.F., 2016. Aquaporin-4 in astroglial cells in the CNS and supporting cells of sensory organs--a comparative perspective. International journal of molecular sciences, 17(9), pp. 1411.

Gunnarson, E., Zelenina, M., Axehult, G., Song, Y., Bondar, A., Krieger, P., Brismar, H., Zelenin, S. and Aperia, A., 2008. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia, 56(6), pp. 587-596.

Hiroaki, Y., Tani, K., Kamegawa, A., Gyobu, N., Nishikawa, K., Suzuki, H., Walz, T., Sasaki, S., Mitsuoka, K., Kimura, K. and Mizoguchi, A., 2006. Implications of the aquaporin-4 structure on array formation and cell adhesion. Journal of molecular biology, 355(4), pp. 628-639.

Ho, J.D., Yeh, R., Sandstrom, A., Chorny, I., Harries, W.E., Robbins, R.A., Miercke, L.J. and Stroud, R.M., 2009. Crystal structure of human aquaporin 4 at 1.8 angstroms and its mechanism of conductance. Proceedings of the National Academy of Sciences, 108(18), pp. 7437-7442.

Hubbard, J.A., Szu, J.I. and Binder, D.K., 2018. The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain research bulletin, 136, pp. 118-129.

Nesverova, V. and Tornroth-Horsefield, S., 2019. Phosphorylation-dependent regulation of mammalian aquaporins. Cells, 8(2), pp. 82.

Zeuthen, T., 2001. How water molecules pass through aquaporins. Trends in biochemical sciences, 26(2), pp. 77-79.

Back to Top