Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Abstract

Elevated basal intracellular calcium (Ca 2 þ ) levels ([Ca 2 þ ] B ) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca 2 þ homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca 2 þ signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca 2 þ homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N ¼ 26) and healthy subjects (N ¼ 17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca 2 þ ] B , lysophosphatidic acid (LPA)-stimulated Ca 2 þ mobilization ([Ca 2 þ ] S ), and thapsigargin-induced store-operated Ca 2 þ entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca 2 þ ] B (F ¼ 8.47; p ¼ 0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca 2 þ ] S and SOCE were significantly reduced (F ¼ 11.1, p ¼ 0.002 and F ¼ 8.36, p ¼ 0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca 2 þ ] B in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca 2 þ mobilization in BLCLs suggests that modulation of intracellular Ca 2 þ homeostasis may be important to the therapeutic action of lithium.

Chronic lithium treatment of B lymphoblasts from bipolar disorder patients reduces transient receptor potential channel 3 levels

“…These observations complement our recent report 9 that chronic Li treatment of BLCLs blunts agonist-and TG-stimulated Ca 2 þ responses, and implicate these protein changes, in part, in this effect. Collectively, these observations illuminate further the spectrum of actions of Li that may be relevant to its mood stabilizing and antimanic effects.…”

“…The mechanism(s) involved in the altered Ca 2 þ homeostasis are still uncertain, but recent observations implicate possible disturbances in one or more of the molecular modules regulating intracellular Ca 2 þ such as mitochondrial Ca 2 þ flux, endoplasmic reticulum (ER) Ca 2 þ storage and release, and store-operated and receptor-operated Ca 2 þ entry (SOCE and ROCE). [7][8][9][10] Observations that lithium (Li) treatment impacts Ca 2 þ signaling and homeostatic mechanisms in neuronal and glial cell models, in addition to other nonexcitable cell models, provide yet another line of support for the notion that intracellular Ca 2 þ dynamics are disrupted in BD. For example, chronic Li treatment attenuated NMDA receptormediated Ca 2 þ influx in neuronal preparations.…”

“…15 Of additional importance, chronic, but not acute, Li treatment of BLCLs at a therapeutic concentration also attenuated G proteincoupled receptor (lysophosphatidic acid, LPA)-mediated and thapsigargin (TG)-induced (SOCE dependent) Ca 2 þ mobilization responses in this surrogate, cellular, pathophysiological model of BD. 9 While the attenuating effects of Li on NMDA-mediated Ca 2 þ influx are mediated through reduced tyrosine phosphorylation of the NR2B subunit of the NMDA gated Ca 2 þ channel, 16 the effect of Li on intracellular Ca 2 þ dynamics in nonexcitable cell models (eg glial cells, platelets, BLCLs) 9,12,13,15 suggests additional mechanisms are likely to be involved in its action. This is particularly important given recent reports of altered glial cell morphometrics and gene expression in postmortem brain of BD patients.…”

“…8 20 Third, chronic treatment of BLCLs from BD and healthy subjects with Li-attenuated LPA and TGinduced Ca 2 þ responses that likely involve SOCE and/or ROCE processes. 9 Recent research directed at elaborating the molecular components and/or mechanisms mediating SOCE and ROCE highlights the key role of several members of the TRP family of cation permeable channels in these processes in nonexcitable cells, such as lymphocytes and platelets. [21][22][23] This superfamily of proteins is comprised of three branches distinguished by sequence homology and functional similarities: TRPC (canonical), TRPV (vanilloid) and TRPM (melastatin).…”

“…The lack of attendant changes in TRPC3 mRNA levels suggests this Li-induced effect is likely mediated through post-translational regulation of TRPC3 levels, changes which in turn may contribute to the attenuating effects of chronic Li treatment on LPA-and TG-evoked intracellular Ca 2 þ responses in BLCLs previously reported. 9 …”