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ELECTRICAL SORTING: THE MISSING LINK BETWEEN MEMBRANE POTENTIAL AND INTRACELLULAR VESICLE TRAFFIC? BEATRICE M. ANNER* Introduction The cellular organelle traffic is dependent on the Na/K gradient and the associated electrical potential across the plasma membrane [I]. However , the link between the peripheral membrane potential and the intracellular membrane traffic is not known. In cells, 50-300-nm vesicles connect the different compartments; they carry, for instance, material from the biosynthetic machinery to the plasma membrane and back to the cell interior [I]. It is well known that the intravesicular organelle traffic is connected to the Na,K-ATPase (EC activity at the plasma membrane. The Na,K-ATPase, or sodium pump, is regulated essentially by the intracellular Na, Mg, and ATP concentrations and by the extracellular K ion concentration. The pump system also carries an extracellular receptor for cardiac glycosides (for a recent review, see [2]). Occupancy of the receptor by a cardioactive steroid, for example, by the convenient water-soluble drug ouabain, immediately blocks the vital coupled Na-extrusion and K-accumulation process that is normally sustained by the plasma membrane Na,K-ATPase, resulting in progressive cellular Na accumulation, K loss, and collapse of the membrane potential . Evidently, the same result is obtained by adding ionophores for Na, K, and H ions to cells; because of their high liposolubility, these chemicals rapidly enter the lipid bilayer, shuttle ions back and forth, and thus destroy the transmembrane ion gradients and potential. Other agents, such as serum, permeabilize plasma membranes by unknown mechanisms . ?Département de Pharmacologie, Centre Médical Universitaire, 1211 Genève 4, Switzerland .© 1987 by The University of Chicago. AU rights reserved. 0031-5982/87/3004-0542$01.00 Perspectives in Biology andMedicine, 30, 4 ¦ Summer 1987 \ 537 Experiments where the Na,K-ATPase activity was either blocked by extracellular ouabain [3] or stimulated by increasing abruptly the intracellular Na concentrations with, for example, the Na-H ionophore monensin [4] or with serum [5], show that receptor recycling [6], circulation of synaptic acetylcholine vesicles [7], the processing of macromolecules and their export from the Golgi [4, 8], and cell proliferation and differentiation [3, 9, 10-12], for instance, are arrested when the internal K concentration is decreased—indicating that the Na/K gradient across the plasma membrane regulates and coordinates the organelle traffic and associated processes. Another argument in favour of a role of ATPases in organelle traffic comes from the finding that the process depends on the presence and concentration ofintracellular ATP [13]. However, the mechanisms by which the peripheral transmembrane Na/K gradient (and the associated membrane potential) regulates the intracellular organelle traffic are not yet known. Obviously, to understand the link among the electrogenic Na,K-ATPase, organelle traffic, and cell division, it is crucial to discover how the Na,K-ATPase organizes and directs the membrane flow in cells. Presumably, the intracellular vesicles are sensitive to the plasma membrane potential because they are themselves electrically charged. To charge vesicles electrically, electrogenic membrane ATPases are the most obvious and dynamic tool. The different possibilities of charging vesicles via electrogenic ATPases are illustrated more easily with experimentally tested artificial lipid vesicles containing electrogenic ATPases. On the basis of an analogy between artificial and natural lipid vesicles —charged selectively via electrogenic ATPases of specific types in defined orientations and numbers—we propose "electrical sorting" as a basic mechanism for the regulation of the intracellular vesicle traffic by the peripheral membrane potential. Electrical sorting means that the intracellular vesicles move according to their characteristic membrane potential resulting from the activity of the electrogenic ATPase they are exporting to or importing from the cell periphery. The migration of specifically charged vesicles along the electrical fields of the cell may be the principle ordering the intracellular traffic. The relevance of three possible types of electrically charged vesicles (positive, negative, or transiently polarized) is discussed. Electrogenic Na,K-ATPase in Artificial Lipid Vesicles It is well known that the Na,K-ATPase is an electrogenic system [14]; the Na flux is accompanied by a current of positive charges resulting from excess Na ions transported in one direction compared to the K ion flux in the...


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pp. 537-545
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