Blood Cells, Molecules, and Diseases (1999) 25(1) Jan 15:9-19 P.J. Romero and E.A. Romero Article No. MD980222 Laboratory of Membrane Physiology. Institute of Experimental Biology. Faculty of Sciences, Central University of Venezuela. Apartado 47114, Caracas 1041-A. Venezuela. Reprint request to: Dr. Pedro J. Romero, Laboratory of Membrane Physiology. Institute of Experimental Biology. Faculty of Sciences, Central University of Venezuela. Apartado 47114, Caracas 1041-A, Venezuela, phone (582)751 0766 x 222, fax (582)753 7087, email: romepe@mixmail.com ISSN No. 1079-9796/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved 9 The Role of Calcium Metabolism in Human Red Blood Cell Ageing: A Proposal Submitted 07/20/98; revised 12/21/98 (communicated by Ernest Beutler, M.D., 12/29/98) Pedro J. Romero, Eneida A. Romero ABSTRACT: The mechanisms of recognition, trapping and destruction of senescent human erythrocytes are not completely understood. Here we discuss some evidences supporting the idea that red cell ageing is closely related to a progressive increase in intracellular ionic Ca. This in turn, is the determining factor of a series of events such as Ca pump proteolysis and opening of the Ca-dependent K channel, that finally lead to the removal of old cells by macrophages at spleen level. © 1998 Academic Press Keywords: erythrocytes, ageing, intracellular Ca, K(Ca)channel, Ca pump proteolysis The human red cell, by lacking nucleus or any two properties just mentioned, deformability and other subcellular organelle, represents the final elasticity, are dramatically affected by Ca ions differentiation stage of the erythroid series. This (3,4). Thus, a rise in internal Ca leads to changes cell ages in the bloodstream during its in cell shape and volume, increased cellular uninterrupted flow through capillaries and rigidity and haemolysis (5,6,7,8,9). Such restricted areas of circulation. The lifespan being alterations seem to arise from Ca interactions about 125 days, after which the aged cell with various molecular targets. These include becomes sequestered at spleen level and is both low-affinity associations with membrane selectively removed by macrophages from the phospholipids (10) and high-affinity ones with reticulo-endothelial system (1). The physiological specific membrane proteins, specially the Ca- mechanisms involved in recognition, trapping dependent K channel (K(Ca) channel) (11) and and destruction of aged human erythrocytes are with some cytoskeletal proteins either directly not completely understood. In the present paper (12) or through calmodulin binding (13,14). we suggest some ideas that may shed light on the Further cellular alterations may also occur problem. physiologically at higher Ca concentrations In order to succeed through restricted areas of through membrane protein crosslinking and microcirculation, such as those found at spleen phosphatidyl inositol degradation (15,16,17). level involving apertures of one-fifth to one-tenth Since internal Ca is subjected to metabolic the cell diameter (2), the human erythrocytes control via an ATP-dependent extrusion must be able to return to their original biconcave- mechanism (Ca pump) (18), it is expected that the disk shape. For this purpose, they are endowed decreased ATP content attained during red cell with an enormous capacity for deformation and ageing, should lead to a raised cellular Ca. This are highly elastic. It is well established that the inference was initially confirmed on in vitro aged