Membrane water transport and aquaporins: Looking back

Abstract

Giuseppe Calamita has kindly asked me to contribute a note for the series of publications related to aquaporins. This topic has consumed my attention for more than a decade, and I am pleased that my colleagues and I were able to play a central role in the story. Those who know the history of our field are familiar with the long-standing controversy that preceded the discovery of water channels. Most scientists felt that water crossed cell membranes by simple diffusion through lipid bilayers. A small group of biophysicists and physiologists believed that diffusion was not sufficient to explain the fast transport of water in tissues such as renal tubules and red cells, and they postulated the existence of membrane water channels. These individuals were ahead of their time and their predictions inspired those of us that followed. Although several are no longer active in our field, and some have passed away, I feel that we should stop for a moment and think about the individuals whose work led to the discovery of aquaporins. The field represents the efforts of an international group of scientists. Following his predecessor, August Krogh, Hans Ussing and his colleagues in Denmark were major contributors to the problem of membrane fluid transport. Arthur K. Solomon in the U.S. was a particularly notable pioneer, and his biophysical studies of membrane water and solute transport drew attention to the field and catalysed major activities by his trainees, including Alan Verkman and others. The deaths of Ussing in 2000 and Solomon in November 2002 silenced brilliant voices who remained interested in membrane transport until their last days. However, the molecular identity of putative water channels remained elusive and caused most scientists to continue to doubt their existence. Despite widespread skepticism, many dedicated investigators pursued the water transport problem: even scientists whose home countries made their lives extremely difficult. Of note, Gheorghe Benga worked on water transport while living in Romania under conditions of cruel political repression; Mario Parisi continued his work in spite of the ‘dirty war’ that consumed his native Argentina; and Guillermo Whittembury remained focused on his research throughout decades of political instability in Venezuela. Others in more comfortable circumstances also made important advances. Amphibian epithelia were investigated by Jacques Bourget and his colleagues in France. Electron microscopy by Lelio Orci and Dennis Brown in Switzerland predicted that intracellular vesicles contained water channels that shuttled to and from the membrane as proposed by James Wade and colleagues in the U.S. Water transport by rodent kidney tubules was investigated by Mark Knepper, Jurgen Schnermann, and James Shafer in the U.S. Clinical studies of vasopressin in humans was pursued by Robert Schrier, Daniel Bichet, and their colleagues in the U.S. and Canada, as well as Sei Sasaki and his colleagues in Japan. Alan Finkelstein's definitive 1986 treatise on water channels should be regarded as an important summary of the studies that made water channels existence unquestionable. Together the efforts of these individuals and others are responsible for our field blossoming as it has. I wish to acknowledge two other individuals whose early insights, in my opinion, were pivotal to the discovery of the first water channel protein: AQP1. The serendipitous discovery that mercuric chloride reversibly inhibits red cell water permeability by Robert Macey, at the University of California at Berkeley in 1970, provided unambiguous evidence that water channel proteins exist. This was indeed opposite to the result Macey expected. I recently chatted with Bob Macey, now an Emeritus Professor at Berkeley, and we shared a special joy knowing that we contributed to a field of research that is fundamental to life. The second individual that I wish to acknowledge is John C. Parker, my attending physician during my hematology fellowship at the University of North Carolina at Chapel Hill. Although John Parker did not study water transport in his own lab, his willingness to listen to a younger scientist describe a newly identified red cell membrane protein of unknown function led to the prediction that it was the long-sought water channel. It is of some comfort to know that John's generous suggestions had already received recognition before his untimely death in 1993. Sooner or later, others would certainly have discovered the identity of the water channel, but the efforts that led to the discovery in our lab in 1991 reflected the contributions of Macey and Parker. Looking back after more than a decade, it is heartening to know that the field has experienced major advances: the aquaporin structures have been solved, aquaporins have been implicated in important human clinical disorders, and aquaporins have been shown to play essential roles in the stress responses of most other life forms. While our lab h