Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status

Abstract

Evidence implicating disturbances of intracellular Ca²⁺ homeostasis has continued to accumulate, with a recent burst of new observations obtained using cultured cell lines from patients with bipolar disorder (BD) suggesting that disturbances occur in receptor-activated and store-operated calcium entry. The potential confounding effects of state of illness and medications on results obtained with various surrogate cellular models is reviewed, and the extent to which findings may reflect trait changes is considered. The role of ER and mitochondria in maintaining intracellular Ca²⁺ homeostasis and in protecting against induction of apoptosis is now better understood. Disrupted Ca²⁺ dynamics found in cell lines from BD patients point to disturbances in these homeostatic control modules in the pathophysiology of a subtype of BD. This notion is further supported by convergence of observations that, on the one hand, show therapeutic concentrations of lithium modifies intracellular Ca²⁺ dynamics in non-human and human cell lines of different ontogeny, and on the other hand, demonstrate that this mood stabilizer modulates anti-apoptotic protein expression that counteracts mitochondrial/ER stress-induced impairment in Ca²⁺ homeostasis.

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.