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AQUAPORIN 4
Aquaporin-4,also known as AQP4,is a water channel protein encoded by the AQP4 gene in humans. AQP4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins are found within the central nervous system(CNS): AQP1, 3, 4, 5, 8, 9, and 11, but more exclusive representation of AQP1, 4, and 9 are found in the brain and spinal cord. AQP4 SHOWS THE LARGEST PRESENCE IN THE CEREBELLUM AND SPINAL CORD GREY MATTER. In the CNS, AQP4 is the most prevalent aquaporin channel, specifically located at the perimicrovessel astrocyte foot processes, glia limitans, and ependyma. IN ADDITION, THIS CHANNEL IS COMMONLY FOUND FACILITATING WATER MOVEMENT NEAR THE CSF AND VASCULATURE.

Aquaporin-4 was first identified in 1986. It was the first evidence of the existence of water transport channels. The method that was used to discover the existence of the transport channels was through knockout experiments. With this technique they were able to show the significant role of AQP4 in CNS injuries and brain water imbalances. IN 1994 THE CHANNEL WAS SUCCESSFULLY CLONED AND INITIALLY NAMED MERCURY-INSENSITIVE WATER CHANNEL.

Structure
The structure of AQP4 consists of six-transmembrane domains and five connecting loops to form the channel. Through x-ray crystallography, it was found that “each AQP4 monomer consists of six helical, membrane-spanning domains and two short helical segments surrounding a narrow aqueous pore.” AT THE NARROWEST POINT THE AQUEOUS PORE MEASURES 2.8 Å, JUST LARGE ENOUGH FOR THE SINGLE-FILE PASSAGE OF WATER MOLECULES. WHILE EACH MONOMER IS INDIVIDUALLY CAPABLE OF WATER TRANSPORT, THE QUATERNARY STRUCTURE OF THE CHANNEL IS A TETRAMER. THE ASSEMBLY OF AQP4 MONOMERS into tetramers is similar to other aquaporin channels. In addition, AQP4 has two distinct structural isoforms located in the CNS: M1 and M23. Both form homo- and hetero-tetramers that are permeable to water. M23 isoforms are larger square arrays in the endfoot membranes of astrocytes compared to M1 isoforms, which are smaller and more unstable. The aquaporin-4 tetramers accumulate to transform into orthogonal arrays of particle (OAPs) in the cell plasma membrane.

Tissue and cellular distribution
AQUAPORIN-4 IS THE MOST COMMON AQUAPORIN IN THE BRAIN, SPINAL CORD, AND OPTIC NERVE. IT is highly expressed in the human body primarily at the end-feet of astrocytes. Additionally, AQP4 can also be located in epithelial cells of many organs throughout the human body, such as the kidney, intestine, salivary glands, sensory organs, and skeletal muscles. In these specific cases of epithelial cell expression, AQP4 is concentrated within the basolateral membrane layer of these locations.

Furthermore, AQP4 also plays a role in the supportive cells of sensory organs, such as the retina, inner ear, and olfactory epithelium. Within the retina, AQP4 is highly concentrated where the processes of Muller cells have a basal lamina around blood vessels and inner limiting membrane and to a lesser degree in the inner and outer plexiform layers.

AQP4 is also expressed in astrocytes and is upregulated by direct insult to the central nervous system. Specifically within the central nervous system (CNS), AQP4 can be found along the spinal cord and serves as the main water channel. The AQP4 channels are highly concentrated in the blood-brain barrier(BBB), as well as in other cerebrospinal fluid barriers.

In the kidneys, AQP4 is PRIMARILY FOUND IN THE INNER MEDULLA, AND SHOWS LITTLE TO NO PRESENCE IN THE OUTER MEDULLA AND CORTEX. IT IS constitutively expressed in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells.

Function
Aquaporin-4’s overall function is to provide fast water transportation as well as maintain homeostatic balance within the central nervous system. THIS CHANNEL CAN TRANSPORT WATER UP TO SPEEDS OF 3E9 MOLECULES PER SECOND. It is the primary water channel protein that reconciles the homeostasis of water in the CNS. AQP4 may be involved in a variety of physiological processes such as waste removal (glymphatic system) and fine-tuning of potassium homeostasis. Water flowing into and out of the brain or spinal cord is assisted by AQP4. Here, AQP4 channels respond passively to osmotic gradients. In addition, they play a role in brain water transport, cell migration, brain edema, metabolism and cell homeostasis.

Other systems are also regulated by AQP4. Within the inner ear, the main role is to provide osmotic balance in supporting epithelium cells within the organ of Corti by recycling K+. Another specific role AQP4 plays is to help odorant molecules bind to target receptors and binding proteins within olfactory epithelium. Within the retina, the role of AQP-4 is to maintain homeostasis. Aquaporin-4 is essential in the formation of memory as well as synaptic plasticity. Other performances that aquaporin-4 is involved in are synaptic plasticity, astrocyte migration, regulation of extracellular space volume, and the homeostasis of potassium.

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