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Annual Review of Physiology

Volume 87, 2025

The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels

  • Virgilio L. Lew1
  • Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; email: [email protected]
  • Vol. 87:257-277 (Volume publication date February 2025)
  • First published as a Review in Advance on October 30, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Calcium ions mediate the volume homeostasis of human red blood cells (RBCs) in the circulation. The mechanism by which calcium ions affect RBC hydration states always follows the same sequence. Deformation of RBCs traversing capillaries briefly activates mechanosensitive PIEZO1 channels, allowing Ca2+ influx down its steep inward gradient transiently overcoming the calcium pump and elevating [Ca2+]. Elevated [Ca2+] activates the Ca2+-sensitive Gardos channels, inducing KCl loss and cell dehydration, a sequence operated with infinite variations in vivo and under experimental conditions. The selected health and disease themes for this review focus on landmark experimental results that led to the development of highly constrained models of the circulatory changes in RBC homeostasis. Based on model predictions, a new perspective emerged, pointing to PIEZO1 dysfunction as the main trigger in the formation of the profoundly dehydrated irreversible sickle cells, the main pathogenic participants in vaso-occlusion, the root cause of sickle cell disease.

Keyword(s): calcium transport, Gardos channels, human red blood cells, PIEZO1, plasma membrane calcium pump, sickle cell disease
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2025-02-10
2025-06-18
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The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels
Annual Review of Physiology 87, 257 (2025); https://doi.org/10.1146/annurev-physiol-022724-105119
/content/journals/10.1146/annurev-physiol-022724-105119
/content/journals/10.1146/annurev-physiol-022724-105119
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