AQP4 Membrane Protein Introduction

Introduction of AQP4

Aquaporin-4, also known as AQP4, is the main water channel of the central nervous system encoded by the AQP4 gene in humans. AQP4 is highly concentrated in the human body primarily at the end of astrocytes, where it participates in the blood-brain barrier (BBB) functional unit. Additionally, AQP4 is also expressed in epithelial cells of many organs throughout the body, such as the kidney, intestine, salivary glands, sensory organs, and skeletal muscles. The structure of AQP4 is characterized by six-transmembrane domains and five connecting loops to form the channel.

Function of AQP4 Membrane Protein

The most well-known function of AQP4 is to provide fast water transportation as well as maintain homeostatic balance within the CNS. It has been recognized that AQP4 can be used as a key molecule in the interaction between astrocytes and brain microvascular endothelial cells to regulate water movement, waste removal, fine-tuning of potassium homeostasis, as well as cell adhesion. Moreover, AQP4 has been considered as a critical contributor to neuroinflammation, which is expressed mainly in the foot processes of pericapillary astrocytes at the blood-brain border (BBB) and brain-cerebrospinal fluid border, and controls the movement of water in the brain. AQP4 is reported to be associated with the pathology of brain edema, which is a disease caused by brain-water imbalance. In addition, the altered AQP4 expression is thought to play a key role in neuroinflammation during brain injury.

Fig.1 Steric fitness of 1,3-propanediol (PDO) inside AQP4. (Yu, 2016)

Application of AQP4 Membrane Protein in Literature

1. Dai W., et al. AQP4 knockout alleviates the lipopolysaccharide induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling. Int J Mol Med. 2018, 42(3):1716-1722. PubMed ID: 29956748
   
   

   This article demonstrates that AQP4 deficiency may relax the proinflammatory cytokine release from astrocytes through SPHK1/MAPK/AKT pathway. It improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.

2. Mizrachi T., et al. NMO-IgG and AQP4 Peptide Can Induce Aggravation of EAMG and Immune-Mediated Muscle Weakness. J Immunol Res. 2018. PubMed ID: 29951558
   
   

   This article reveals that immunization with the neuromyelitis optica (NMO) autoantigen AQP4 through augmented inflammatory response can increase disease severity in EAMG mice, which may explain exacerbation or increased susceptibility of patients with one autoimmune disease to develop the additional autoimmune syndrome.

3. Guo J., et al. Aquaporin 4 Silencing Aggravates Hydrocephalus Induced by Injection of Autologous Blood in Rats. Med Sci Monit. 2018, 24: 4204-4212. PubMed ID: 29921834
   
   

   In this study, the authors use a rat model of hydrocephalus to demonstrate that AQP4 is over-expressed in hydrocephalus and silencing AQP4 can aggravate the hydrocephalus, indicating that AQP4 plays a protective role against hydrocephalus.

4. Zhao F., et al. Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses. J Neuroinflammation. 2018, 15: 157. PubMed ID: 29793504
   
   

   This article demonstrates that AQP4 deletion can protect the blood-brain barrier (BBB) integrity by reducing inflammatory responses, which is realized by the upregulation of PPAR-γ expression and attenuation of proinflammatory cytokine release. So, the authors suggest that the reduction of AQP4 may be protective in acute severe hypoglycemia.

5. Li Y., et al. ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation. Neurochem Res. 2018. PubMed ID: 29767275
   
   

   The authors use a rat ischemic stroke (IS) model to reveal that increasing the Aldehyde dehydrogenase 2 (ALDH2) activity can improve brain edema, infarct volumes, and reduce neurological impairment, which is related to 4-HNE clearance and AQP4 down-regulation.

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Reference

1. Yu L, et al. (2016). 1,3-Propanediol binds inside the water-conducting pore of aquaporin 4: Does this efficacious inhibitor have sufficient potency? J Syst Integr Neurosci. 2: 91-98.

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