The Role of CaMKII in Calcium-Activated Death Pathways in Bone Marrow B Cells

Abstract

Calcium is an essential signaling molecule in developing B cells, thus altering calcium dynamics represents a potential target for toxicant effects. GW7845, a tyrosine analog and potent peroxisome proliferator-activated receptor γ agonist, induces rapid mitogen-activated protein kinase (MAPK)-dependent apoptosis in bone marrow B cells. Changes in calcium dynamics are capable of mediating rapid initiation of cell death; therefore, we investigated the contribution of calcium to GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre-B cell line (BU-11) with GW7845 (40 μM) resulted in intracellular calcium release. Multiple features of GW7845-induced cell death were suppressed by the calcium chelator BAPTA, including MAPK activation, loss of mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation. A likely mechanism for the calcium-mediated effects is activation of CaMKII, a calcium-dependent MAP4K. We observed that three CaMKII isoforms (β, γ, and δ) are expressed in lymphoid tissues and bone marrow B cells. Treatment with GW7845 increased CaMKII activity. All features of GW7845-induced cell death, except loss of mitochondrial membrane potential, were suppressed by CaMKII inhibitors (KN93 and AIP-II), suggesting the activation of multiple calcium-driven pathways. To determine if CaMKII activation is a common feature of early B cell death following perturbation of Ca(2+) flux, we dissected tributyltin (TBT)-induced death signaling. High-dose TBT (1 μM) is known to activate calcium-dependent death. TBT induced rapid apoptosis that was associated with intracellular calcium release, CaMKII activation and MAPK activation, and was inhibited by AIP-II. Thus, we show that early B cells are susceptible to calcium-triggered cell death through a CaMKII/MAPK-dependent pathway.

Metformin Protects Skeletal Muscle from Cardiotoxin Induced Degeneration

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CaMKII in cerebral ischemia

“…However, as for the neuronal CaMKII targets discussed above, some of these links to apoptosis can promote cell death while others promote survival. CaMKII has been shown to be involved in mediating apoptosis induced by TNFα and UV irradiation[184] microcystein (phosphatase inhibitor)[185, 186], GW7845 (PPARγ agonist)[187], ER stress[188], TRAIL[189], and -in cardiac myocytes- by isoproterenol (β adrenergic agonist)[190, 191], ouabain (Na + /K + -ATPase inhibitor)[192], oxidative stress (induced by H 2 O 2 or angiotensin II)[193–195], and cardiac ischemia[196–198]. In these cases, CaMKII inhibition attenuated apoptotic death.…”

Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics

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