Aquaporin-4 (AQP4) is a protein that functions as a water channel, allowing water molecules to move rapidly across cell membranes. AQP4 plays a fundamental role in maintaining fluid balance within various tissues.
How AQP4 Channels Water
AQP4 belongs to the aquaporin family of proteins, which are specialized channels for water transport across cell membranes. AQP4 forms pores that allow water molecules to pass through. Its structure consists of six transmembrane domains and five connecting loops that create the channel.
The channel’s design ensures high selectivity for water molecules, excluding larger molecules and charged ions like protons. This selectivity is achieved through specific structural features within the pore, including a narrow constriction of approximately 2.8 Å and an arginine residue that blocks proton entry. Water movement through AQP4 channels is passive, meaning it does not require cellular energy, and occurs in response to osmotic gradients. AQP4 can transport water at speeds up to 3 billion molecules per second.
Where AQP4 is Found in the Body
AQP4 is widely distributed throughout the human body, with a particularly high concentration in the central nervous system (CNS), which includes the brain, spinal cord, and optic nerve. In the brain, AQP4 is primarily located in the end-feet of astrocytes, a type of glial cell, where they make contact with blood vessels and the cerebrospinal fluid (CSF) barriers. This positioning is important for regulating brain water homeostasis and facilitating the glymphatic system, which helps clear waste products from the brain.
Beyond the CNS, AQP4 is also found in other organs and tissues, where it supports specific physiological functions. These include:
- Eyes: Present in the retina and optic nerve, contributing to fluid balance and visual processing.
- Inner ear: Helps maintain osmotic balance in supporting cells within the organ of Corti, involved in hearing.
- Kidneys: Found in the basolateral membranes of principal collecting duct cells, facilitating water reabsorption.
- Skeletal muscle, salivary glands, and gastric parietal cells: Identified in these areas, indicating its involvement in fluid regulation.
AQP4’s Role in Health and Disease
Dysfunction or targeting of AQP4 has implications for various health conditions, particularly neurological disorders. A well-known association is with Neuromyelitis Optica Spectrum Disorder (NMOSD), an inflammatory autoimmune disease affecting the CNS. In NMOSD, the immune system produces AQP4-IgG autoantibodies that target and bind to AQP4 proteins, primarily on astrocytes. This binding can lead to astrocyte damage, often through complement activation, resulting in inflammation and damage to the optic nerves and spinal cord.
AQP4 also plays a role in brain edema, or swelling, which can occur after events like stroke or traumatic brain injury. In cytotoxic brain edema, AQP4 facilitates water entry into brain cells, while in vasogenic edema, it is involved in the clearance of excess fluid from the brain. Understanding AQP4’s role in different types of brain edema is important for developing therapeutic strategies. Research is exploring AQP4’s involvement in other neurological conditions, including its link to neurodegenerative diseases like Alzheimer’s disease. The ability to detect AQP4-IgG antibodies is a diagnostic marker for NMOSD, and ongoing research aims to develop therapies that target AQP4 to manage fluid imbalances and reduce inflammation in associated diseases.