Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies

Abstract

In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na⁺,K⁺-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na⁺,K⁺-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na⁺,K⁺-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na⁺,K⁺-ATPase in dopaminergic system pathologies-both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson's disease, we extend our discussion to the role of Na⁺,K⁺-ATPase and cardiotonic steroids in neurodegenerative diseases as well.

Keywords: Na+,K+-ATPase; bipolar disorder; cardiotonic steroids; depression; dopamine; neurodegeneration.

Figure 1

Potential consequences that NKA dysfunction, whether from high CTS or other pathological conditions, may have on dopaminergic signaling. Green arrows represent downstream activation, while red arrows represent inhibitory processes. Short black arrows to the right of a given element denote increased activation or increase in concentration (pointing up), or decreased activation or decrease in concentration (pointing down).

Figure 2

OS caused by non-inhibitory concentrations of CTS, mediated via the Src-ERK1/2 pathway (A); possible consequences of chronic elevation of endogenous (non-inhibiting NKA) CTS concentrations in dopaminergic system neurons (B). Green arrows represent downstream activation, while red arrows represent inhibitory processes. Short black arrows to the right of a given element denote increased activation or increase in concentration (pointing up), or decreased activation or decrease in concentration (pointing down).