The clinical relevance of research on fundamental cellular processes may require many years of work before the knowledge is medically useful. Among the most fundamental physiological processes essential for life are the mechanisms used by cells, tissues, and organs of the body to manage water content and flow. Water movement in tissues requires its transport across the cell membrane. Strict regulation of cellular salt and water content is essential for virtually all metabolic activity, so the cell membrane must manage the transport of these substances into and out of the cell. By 1935, it was suggested that proteins embedded within the cell membrane were responsible for a variety of cellular functions including sodium and water flow.
The following decades of research demonstrated that transport of salts and small organic molecules, such as glucose, is accomplished via two types of membrane proteins: channels, which permit rapid flow via diffusion through molecular sized pores; and carriers, which bind the transported molecules and shuttle them across the membrane. Although its existence was predicted more than 50 years earlier, a protein specialized for water transport across membranes remained an elusive target. In 1983, various transport proteins were proposed to double as the putative water channel, but none were demonstrated experimentally. Then in 1992, Dr. Peter Agre discovered a small, abundant protein in red blood cell membranes that also was identified in kidney tubules. Subsequent isolation, purification, and insertion of this protein into membranes confirmed its function as a water channel, and it later was named aquaporin-1.
Dr. Agre established that aquaporin-1 (AQP1) is one member of a family of ten mammalian aquaporins, and hundreds of similar proteins have been identified in virtually all forms of life. His work has progressed rapidly as knowledge of the specific cellular locations of the various forms of aquaporins has generated a more accurate picture of how water transport is maintained and regulated in tissues that have high rates of fluid transport, such as kidney, and the salivary, lacrimal and sweat glands, as well as those tissues that must maintain strict regulation of water content, such as the brain, the cornea and lens of the eye, and the respiratory tract. Clinician scientists are beginning to identify a multitude of diseases that are associated with genetic defects or altered regulation of various aquaporins.
The identification and localization of aquaporin family members has revealed the complexity that has evolved to manage salt and water membrane permeability. Future research will continue to explore the regulatory pathways that control these important transporters as well as their function. Furthermore, scientists have just begun to identify the role of aquaporins involved in a number of diseases, e.g. Sjögren’s syndrome, an autoimmune disease that drastically reduces tear flow, some kidney diseases, congestive heart failure, and cirrhosis. Understanding how their function is disrupted will lead to new therapeutic targets. For his work Dr. Agre, an NIH and NEI grantee who has led much of the effort to understand aquaporins, shared the 2003 Nobel Prize in chemistry with another NIH grantee, Dr. Roderick MacKinnon.
Posted: February 2011