Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status
Introduction
During the past decade fundamental understanding of the cellular and molecular basis of neuronal and glial function has evolved rapidly illuminating many of the molecular mechanisms involved in such processes as cellular differentiation, axonal growth, synapse formation, neuroplasticity, and apoptosis. This has been a major force driving the marked paradigmatic shift in thinking regarding the genesis and pathophysiology of bipolar disorders (BD). Thus, it is that investigation of the pathophysiological basis of BD has focused on the molecular infrastructure underlying the intracellular signaling cascades and transduction mechanisms seminal to these processes, and to the functional integrity of neurons and glia. Not surprising, disturbances of intracellular calcium (Ca2+) signaling and homeostasis have come to light [1] given its crucial role in a myriad of cellular functions [2], [3], [4]. This is despite the fact that investigators have had to rely heavily on surrogate cellular and animal models to piece together the nature and mechanisms involved, given that the dynamics of Ca2+ signaling must be measured in living cells.
In this review, we knit together the diverse body of experimental findings which indicate that intracellular Ca2+ homeostasis is altered in at least some subtypes of BD, and consider some of the molecular mechanisms implicated. This is grounded on an initial, brief overview of the salient aspects of intracellular Ca2+ signaling and homeostatic regulation most relevant to the interpretation of the results of clinical, biochemical and molecular investigations of abnormal intracellular Ca2+ dynamics that have been reported in BD, to date.
Section snippets
Dynamics of calcium signaling
Intracellular Ca2+ signaling operates in a concentration range 3–4 orders of magnitude lower than that in the extracellular space [4]. Maintenance of this gradient is critical to cellular integrity; even minor distortions if sustained over prolonged periods can activate cell death signaling programs and escape the capacity of molecular rescue mechanisms [5]. A variety of molecular processes have evolved to sustain the critical intracellular Ca2+ concentration ([Ca2+]i) window, and to contain
Ca2+ homeostasis disturbances in bipolar disorder
That disturbances of intracellular Ca2+ dynamics occur in BD and major depressive disorder (MDD) is supported by a substantive and growing body of direct and indirect evidence, although the mechanisms responsible are still poorly understood. Historically, the notion that Ca2+ homeostasis may be disturbed in BD was first advanced by Weston and Howard [52] who compared serum and cerebrospinal fluid (CSF) electrolyte levels between groups of bipolar patients in depressed versus manic phases of
Modulation of intracellular Ca2+ signaling by lithium
In line with the hypothesis that altered intracellular Ca2+ homeostasis may be an important aspect of the pathophysiology of BD, a large body of data has accumulated demonstrating that lithium exerts significant modulatory effects on intracellular Ca2+ dynamics in a wide variety of cellular preparations including neurons in primary cultures. For instance, chronic, but not acute, exposure of mouse astrocytes in primary cultures to a clinically relevant concentration of lithium decreased basal
Summary and conclusions
Guided by advancing knowledge of the molecular mechanisms regulating intracellular Ca2+ signaling, continued scrutiny of intracellular Ca2+ homeostasis, particularly using surrogate cellular models that minimize or eliminate confounding treatment and state-dependent factors, has contributed important new observations on the nature of the abnormalities involved. Burgeoning evidence supports the notion that chronic lithium and valproate exert neuroprotective actions mediated through effects on
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