Structural properties of vacuolar proton pumps.

It is well established that acidification within the collecting duct system is effected by means of a sodium-independent, electrogenic proton translocating ATPase [11. This proton pump belongs to a new class of proton pumps, termed vacuolar, which encompasses a group of very closely related enzymes that are widespread in distribution. Indeed, the vast majority of enzymatic activity relevant to these pumps in mammalian systems is extrarenal, and vacuolar proton pumps have been localized to most intracellular organelles, including clathrin coated vesicles, endosomes, lysosomes, synaptic vesicles, chromaffin granules, and endoplasmic reticulum [2—4]. Plasma membrane localizations, in addition to the kidney, have been reported in osteoclasts [5] and macrophages [6]. Much of our knowledge of the structure and function of vacuolar proton pumps is derived from investigations in tissues other than the kidney. This is due, in large part, to the difficulty in isolating the enzyme from renal microsomes. Nonetheless, it has become apparent that the putative isoforms of vacuolar and proton translocating ATPase are intensely related and thus extrapolations from investigations of pump function conducted in extra-renal membranes are likely pertinent to the issue of the structure and function of the renal proton pump. From such studies, a rather crude structural overview of the vacuolar proton pump has emerged over the past several years. Agreement has been reached among various groups of investigators that these pumps are large hetero-oligomers [4]. Initial reports of putative subunit composition ranged from three to more than 15 [7—12]. At present, there is an emerging consensus that eight to nine different polypeptides are present in most, if not all vacuolar proton translocating ATPases. For a number of subunits, function has been at least tentatively ascribed, and primary structure is known for six of the subunits. In this review, data from studies conducted with widely divergent membrane preparations have been assembled to present a working model of pump function. In addition, issues relevant to the enzymatic regulation of pump function are discussed.