The Nobel Prize in Chemistry for 2003.

Abstract

The Royal Swedish Academy of Sciences awarded The Nobel Prize in Chemistry for 2003 jointly to Peter Agre and Roderick MacKinnon for their discoveries concerning ‘channels in cell membranes' being of fundamental importance for understanding how water and ions move through these membranes. Agre discovered and characterized the first water channel protein and MacKinnon has elucidated the structural and mechanistic basis for ion channel function. Lipid bilayer membranes are generally impermeable to water, ions and other polar molecules, yet, in many instances, such entities need to be rapidly and selectively transported across a membrane, often in response to an extra- or intracellular signal. Transport along a concentration gradient is mediated by membrane channel proteins, whereas transport against a concentration gradient is mediated by membrane pumps such as the Na+/K+ ATPase (a protein discovered in 1957 by Jens Skou, who received the Nobel Prize in chemistry in 1997). Water channels allow the cell to regulate its volume and internal osmotic pressure and are needed when water must be retrieved from a body fluid, such as when urine is concentrated in the kidney. Water channels are found in all organisms, from bacteria to man, and are crucial for life. The water channels were discovered by chance by Agre in the mid-1980s when he was studying blood group antigens from the red blood cell membrane. Agre's unexpected discovery of the aquaporins revolutionized the study of water transport and laid a firm biochemical foundation for a very important area of physiology and medicine. Aquaporin-like proteins have since been found across taxonomic kingdoms. In humans alone, there are at least 11 different aquaporin-like proteins, many of which have been linked to various diseases, some of them inflammatory and autoimmune in nature (J Physiol 2002;542:3–16). Plants have an even higher number of aquaporins. The physiological importance of the aquaporins is perhaps most conspicuous in the kidney, where 150–200 l of water need to be reabsorbed from the primary urine each day. This is made possible mainly by the AQP1 and AQP2 aquaporins. Diseases that have been linked to changes in levels of these aquaporins are nephrogenic diabetes insipidus, congestive heart failure and Sjögren's syndrome (Trends Endocrinol Metab 2002;13:355–360; Arthritis Rheum 2003;48:1167–1168). Other areas that are topics for current studies are searches for disease phenotypes that may result from mutations or perturbation of specific aquaporins. Additions to this list are loss of major blood group antigens, cataracts, renal tubular acidosis and brain oedema. As early as 1890, Wilhelm Ostwald (Nobel laureate in chemistry 1909) suggested, based on experiments with artificially prepared colloidal membranes, that electrical currents in living tissues might be induced by ions moving across cellular membranes (Z Phys Chem 1890;6:71–82). A breakthrough came in 1998, when MacKinnon succeeded in determining the first high-resolution structure of an ion channel, the KcsA K+ channel from Streptococcus lividans (Science 1998;280:69–77). The design of the selectivity filter was seen to be perfectly adapted to the job of desolvating potassium ions while keeping smaller sodium ions out, thus explaining the high K+ selectivity and the high transport rate. As already shown by Hodgkin and Huxley (Nobel laureates in 1963 in physiology/medicine) in the early 1950s, in excitable cells such as nerve, muscle and endocrine cells, voltage-induced gating of ions channels is the central principle of activation. Very recently, MacKinnon solved the structure of the archaeal voltage-gated K+ channel KvaP in a complex with antibody fragments directed against the voltage sensor domain (Nature 2003;423:33–41). Interestingly, the antibody fragments appear to have pulled the sensor domains away from the ion channel itself. MacKinnon's structural and mechanistic work on K+ channels has unravelled the molecular underpinnings of ion selectivity, gating and inactivation and has uncovered entirely new possibilities for very detailed biochemical, biophysical and theoretical studies of ion channel function. His discoveries also provide a firm basis for a molecular understanding of many neurological, muscular and cardiac diseases, opening up new possibilities for drug design. In conclusion, this year's Nobel Prize in chemistry has been awarded to two scientists involved in fundamental studies of membrane channels. The rapid progress in our understanding of membrane channel function over the past decade is in large part due to the discoveries concerning water and ion channels. Agre's discovery of the aquaporin water channels and MacKinnon's detailed structural and mechanistic studies of K+ channels are singular achievements that have made it possible for us to see these exquisitely designed molecular machines in action at the atomic level. It is clear that the Nobel Assembly has awarded a prize to a research field that is mature and closely related to molecular immunology, inflammation and investigations in some immune-mediated disease mechanisms.