Systematic Review of the Role of Aquaporin 4 M1 and M23 Isoforms in Edemas and Tumors

Abstract

Aquaporin 4 (AQP4) is a water transporting channel protein expressed in cells of the brain, spinal cord, optic nerve, and epithelial cells in various organs where it serves to maintain homeostasis. In this review, primary qualitative data was reviewed regarding 2 translational isoforms of AQP4, M1 and M23. PubMed was searched for all relevant articles spanning from 2009-2020. Eligible papers for systematic review were those including the words “AQP4”, “M1”, and “M23”, which resulted in 69 possible articles. For the purpose of this review, we excluded papers investigating Neuromyelitis Optica (NMO) leaving us with 44 possible articles. In this review we discuss AQP4s structure, function, and role in cytotoxic and vasogenic brain edema and tumors. AQP4 is made up of 6 alpha helices connected by 5 interhelical loops, with loops B and E containing the asparagine-proline-alanine (NPA) motifs. Both NPA motifs are hydrophobic and create a pattern much like an hourglass figure that allows for water selectivity. AQP4 is responsible for controlling the bidirectional fluid exchange at the blood brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier. AQP4 also contributes to cytotoxic and vasogenic edema and peritumoral brain edema (PTBE) through transport of water across the microvasculature following bodily injury. It also influences tumorigenesis in the brain and spine. Multiple translation start sites on AQP4 form its two isoforms M1 and M23. These isoforms have different selectivity rates and thus are a contributing factor in causing and preventing edema formation. Beyond expressing information regarding APQ4 and its isoforms, this review seeks to contribute a novel synthesis and provide new connections of the current knowledge to the role of M1 and M23 in edemas and tumors.