Critical Roles of the Na+/K+-ATPase in Apoptosis and CNS Diseases

Abstract

The Na+/K+-ATPase is a transmembrane protein that serves as the primary electrogenic ion transporter in the plasma membrane of all mammalian cells. In addition to this critical ubiquitous function, the Na+/K+-ATPase is also essential for several important tissue-specific functions, which include Na+ resorption in the kidney, muscular contraction in cardiac and skeletal myocytes, and membrane repo-larization. Although the Na+/K+-ATPase was first discovered in neuronal tissue, its function has been much more extensively characterized in cardiac and renal tissues, and the roles of the Na+/K+-ATPase as a novel drug target in these systems have been recently reviewed (1, 2). The goal of this chapter is to review the function and dysfunction of the plasma membrane Na+/K+-ATPase in the context of neuronal diseases. More specifically, this chapter will outline the structure, function, and regulation of the Na+/K+-ATPase under normal as well as hypoxic/ischemic conditions. We will review recent evidence on the relationship between the Na+/K+-ATPase and K+ homeostasis in neuronal apoptosis, outline the emerging role of ouabain and other Na+/K+-ATPase inhibitors as endogenous hormones, which activate specific signal transduction cascades by binding to the Na+/K+-ATPase, and evaluate the impact of these signal transduction functions on the role of Na+/K+-ATPase in CNS diseases.