Na+, K+-ATPase Signaling and Bipolar Disorder

Abstract

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD.

Imbalance between Omega-6 and Omega-3 Polyunsaturated Fatty Acids in Early Pregnancy Is Predictive of Postpartum Depression in a Belgian Cohort

“…The sodium-potassium pump (Na + /K + -ATPase) is an example of a membrane protein whose activity is specifically related to the DHA composition. A disturbance of its activity has been associated with mood disorders [29,30].…”

Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

“…Furthermore, in this current study, I have provided compelling evidence that NKA activity is vital for normal brain development and loss of NKA activity is associated with cognitive impairment, neurological and developmental disorders [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]. Indeed, loss of NKA activity represents an interconnected molecular function in neurodevelopmental and neuropsychiatric and neurodegenerative disorders including; Down syndrome, Alzheimer’s, Parkinson’s and Huntington’s disease, as well as epilepsy, autism, schizophrenia, mood and depressive disorders.…”

“…Given the importance of NKA in cellular homeostasis and intracellular signaling, impairment or downregulation of NKA activity has been implicated in many pathophysiological conditions, including asthma and allergic diseases, metabolic disorders, cancer, cardiovascular and degenerative brain diseases, as well as neuropsychological disorders [3,6,7,8,9,10,11,12,13,14], as illustrated in Figure 1 and discussed below.…”

“…Furthermore, a great body of evidence associates neurotoxicity with a reduction of NKA activity, suggesting that reduction in NKA activity may be a link between several common neurotoxic mechanisms [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]. Loss of NKA is associated with autism [65,66,69]; Alzheimer’s disease [66,80,81]; Parkinson’s disease [82]; amyotrophic lateral sclerosis [70,82]; Down syndrome and Huntington’s disease [69]; depression and mood disorders [71,72,73,74]; bipolar disorder [14,75,76] and schizophrenia [15,77,79], as well as in animal models of depression [83,84]. Interestingly, NKA activity has been found to be significantly lower in subjects with phenylketonuria [85], a disease associated with intellectual disability, seizures, behavioural problems and mental disorders.…”

Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

“…The double arrow between the CSs and Na + , K + -ATPase boxes indicates the feedback in the regulation of the ECS level and Na + , K + -ATPase isoforms' expression. The Na + , K + -ATPase-ECS interaction leads to changes in the membrane electrical potential, and the activation of mitogen-activated protein kinase (ERK, or MAPK), protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer (NFκB) [19,71], which modifies neuronal activity and neurotransmission that, in turn, participate in the regulation of behavior and BD. The oxidative stress and inflammation, which are also involved in the Na + , K + -ATPase-ECS interaction [6,29], may add to the compromised brain biochemistry and support the vicious circle of depression in BD.…”