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This is for BIOL 3501 assignment due 3/27/17.

Aquaporin-4 (AQP4)
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. Only limited aquaporins are found within the CNS: AQP1, 3, 4, 5, 8, 9, and 11, but only AQP1, 4, and 9 are exclusively found in the brain and spinal cord .Focusing on AQP4, which has the most water channels in the CNS, are specifically located at the perimicrovessel astrocyte foot processes, glia limitans, and ependyma.

Aquaporin-4 was first discovered in 1986, it was the first evidence for the existence of water transport channels. The method they performed to show evidence of AQP4 was a knockout experiment. With this technique they were able to show the significant role of AQP4 in the CNS injuries and brain water imbalances.

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.” Similar to other aquaporin in that AQP4 monomers assemble into tetramers. In addition, has two distinct structural isoforms located in the CNS called M1 and M23, both forming homo- and hetero-tetramers that are permeable to water. M23 isoforms are larger square arrays in the endfood membranes compared to M1 isoforms, which are smaller and more unstable square arrays. The Aquaporin-4 tetramers accumulate to transform into orthogonal arrays of particle (OAPs) in the cell plasma membrane.

Location
Aquaporin-4 is highly expressed in the human body primarily at the end-feet of astrocytes. Additionally, AQP4 can also be found 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 concentration is found 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. In the inner ear,

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 found to be highly concentrated in the blood-brain barrier (BBB), as well as in other cerebrospinal fluid barriers.

Function
Aquaporin-4’s overall function is to provide fast water transportation as well as maintain homeostatic balance within the central nervous system. 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 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.

Disease and Pathology
Aquaporin-4 has a niche in several diseases, however,  AD, ALS, PD, MS, NMO, epilepsy, TBI, and stroke have shown prominent relations in alterations in AQP4 expression for causation of these diseases. It is known that Alzheimer patients have plaques called amyloid deposits that are found in the blood vessels of the patients. This condition is referred to as cerebral amyloid angiopathy, or CAA. The severity of CAA increases or decreases depending on aquaporin-4 expression. When there is an decrease in AQP4, CAA severity increases and vice versa. Since AQP4 is identified mainly in astrocytes, they can be found to have a role in the regulation of brain edema. The astrocytes are found to be involved in cytotoxic edema typically found in brain tumors, focal inflammation, abscess and late ischemia. Any damage to astrocytes in the brain causes upregulation of AQP4. Moreover, AQP4 helps to form cytotoxic edema and eliminates vasogenic edema (disruption of BBB). In early stages of brain injury or insult, AQP4 helps to protect the brain and BBB and maintain the BBB integrity in development and mature individuals. In intracerebral hemorrhages (ICH), the aquaporin-4 serves to improve neurological function. It increases survival rate and inhibits neuronal death and apoptosis after ICH. Amyotrophic lateral sclerosis (ALS) patients experience an increase in aquaporin-4 expression in the brainstem, cortex, and gray matter of the spinal cord which results in swollen astrocytes. The water and potassium levels are disrupted due to alterations in AQP4, which also disrupts blood-brain barrier integrity.

Mutations
Mutations in aquaporin-4 display cognition problems specifically in memory deficits. There is disruption in memory consolidation as well as disruption between memory acquisition and spatial recognition. Moreover, aquaporin-4 mutation reveals that there is deficit in object placement when it comes to movement of an object to a new location. In some cases, over expression of AQP4 has been associated with some malignant brain tumors.