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Critical Roles of Ca2+ and K+ Homeostasis in Apoptosis

  • Chapter
The Cell Cycle in the Central Nervous System

Part of the book series: Contemporary Neuroscience ((CNEURO))

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Abstract

Apoptosis occurs during the development, aging, and in various disease states. The apoptotic biochemical cascade involves activation of caspases, release of mitochondrial apoptotic factors, and nuclear DNA fragmentation, subjecting to regulation by pro- and antiapoptotic Bcl-2 genes. Emerging evidence supports that apoptosis is controlled by ionic mechanisms involving changes in Ca2+ and K+ homeostasis. It is proposed that Ca2+ changes in cell organelles mainly the endoplasmic reticulum (ER) and mitochondria, but not the cytosolic Ca2+, play critical roles in regulating and mediating apoptosis events. The Bcl-2 family members control the ER-mitochondria amplification loop of apoptosis. Overexpression of Bcl-2 or deficient for Bax and Bak lowers ER resting Ca2+ concentration ([Ca2+]ER) and secondarily decreased mitochondrial Ca2+ uptake. This fine-tuning of Ca2+ compartmentalization provides a mechanism for temporal and spatial regulation of Ca2+ signaling in apoptosis. Compelling evidence also reveals that excessive K+ efflux and intracellular K+ depletion are critical steps in apoptotic cell shrinkage and downstream events. Physiological concentration of intracellular K+ acts as a repressor of apoptotic effectors. A huge loss of cellular K+, likely a common event in apoptosis of many cell types, may serve as a disaster signal allowing the execution of the suicide program by activating key events in the apoptotic cascade including caspase cleavage, cytochrome-c release, and endonuclease activation. The proapoptotic disruption of K+ homeostasis can be mediated by overactivated K+ channels and, most likely, accompanied by reduced K+ uptake as a result of dysfunction of Na+,K+-adenosine triphosphatease. In addition to the K+ channels in the plasma membrane, mitochondrial K+ channels also play important roles in apoptosis. Investigations on the Ca2+ and K+ regulation of apoptosis, together with the molecular mechanism, have provided a more comprehensive understanding of the apoptotic mechanism. Further studies are needed to address new questions and may afford novel therapeutic strategies for apoptosis-related diseases.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Medical University of South Carolina, Charleston, SC

    Shan Ping Yu MD, PhD

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  1. Shan Ping Yu MD, PhD
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  1. The Cleveland Clinic Foundation, Cleveland, OH

    Damir Janigro PhD

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© 2006 Humana Press Inc., Totowa, NJ

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Yu, S.P. (2006). Critical Roles of Ca2+ and K+ Homeostasis in Apoptosis. In: Janigro, D. (eds) The Cell Cycle in the Central Nervous System. Contemporary Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-021-8_10

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