Studies done many years ago established unequivocally the key role of calcium as a universal second messenger. In contrast, the second messenger roles of reactive oxygen and nitrogen species have emerged only recently. Therefore, their contributions to physiological cell signaling pathways have not yet become universally accepted, and many biological researchers still regard them only as cellular noxious agents. Furthermore, it is becoming increasingly apparent that there are significant interactions between calcium and redox species, and that these interactions modify a variety of proteins that participate in signaling transduction pathways and in other fundamental cellular functions that determine cell life or death. This review article addresses first the central aspects of calcium and redox signaling pathways in animal cells, and continues with the molecular mechanisms that underlie crosstalk between calcium and redox signals under a number of physiological or pathological conditions. To conclude, the review focuses on conditions that, by promoting cellular oxidative stress, lead to the generation of abnormal calcium signals, and how this calcium imbalance may cause a variety of human diseases including, in particular, degenerative diseases of the central nervous system and cardiac pathologies.

We report here the presence of an NADPH oxidase (NOX) activity both in intact and in isolated transverse tubules and in triads isolated from mammalian skeletal muscle, as established by immunochemical, enzymatic, and pharmacological criteria. Immunohistochemical determinations with NOX antibodies showed that the gp91^phox membrane subunit and the cytoplasmic regulatory p47^phox subunit co-localized in transverse tubules of adult mice fibers with the α_1s subunit of dihydropyridine receptors. Western blot analysis revealed that isolated triads contained the integral membrane subunits gp91^phox and p22^phox, which were markedly enriched in isolated transverse tubules but absent from junctional sarcoplasmic reticulum vesicles. Isolated triads and transverse tubules, but not junctional sarcoplasmic reticulum, also contained varying amounts of the cytoplasmic NOX regulatory subunits p47^phox and p67^phox. NADPH or NADH elicited superoxide anion and hydrogen peroxide generation by isolated triads; both activities were inhibited by NOX inhibitors but not by rotenone. NADH diminished the total thiol content of triads by one-third; catalase or apocynin, a NOX inhibitor, prevented this effect. NADPH enhanced the activity of ryanodine receptor type 1 (RyR1) in triads, measured through [³H]ryanodine binding and calcium release kinetics, and increased significantly RyR1 S-glutathionylation over basal levels. Preincubation with reducing agents or NOX inhibitors abolished the enhancement of RyR1 activity produced by NADPH and prevented NADPH-induced RyR1 S-glutathionylation. We propose that reactive oxygen species generated by the transverse tubule NOX activate via redox modification the neighboring RyR1 Ca²⁺ release channels. Possible implications of this putative mechanism for skeletal muscle function are discussed.

Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation.

Calcium and iron play dual roles in neuronal function: they are both essential but when present in excess they cause neuronal damage and may even induce neuronal death. Calcium signals are required for synaptic plasticity, a neuronal process that entails gene expression and which is presumably the cellular counterpart of cognitive brain functions such as learning and memory. Neuronal activity generates cytoplasmic and nuclear calcium signals that in turn stimulate pathways that promote the transcription of genes known to participate in synaptic plasticity. In addition, evidence discussed in this article shows that iron deficiency causes learning and memory impairments that persist following iron repletion, indicating that iron is necessary for normal development of cognitive functions. Recent results from our group indicate that iron is required for long‐term potentiation in hippocampal CA1 neurons and that iron stimulates ryanodine receptor‐mediated calcium release through ROS produced via the Fenton reaction leading to stimulation of the ERK signaling pathway. These combined results support a coordinated action between iron and calcium in synaptic plasticity and raise the possibility that elevated iron levels may contribute to neuronal degeneration through excessive intracellular calcium increase caused by iron‐induced oxidative stress. IUBMB Life, 59: 280‐285, 2007

A great body of experimental evidence collected over many years indicates that calcium has a central role in a variety of neuronal functions. In particular, calcium participates in synaptic plasticity, a neuronal process presumably correlated with cognitive brain functions such as learning and memory. In contrast, only recently, evidence has begun to emerge supporting a physiological role of reactive oxygen (ROS) and nitrogen (RNS) species in synaptic plasticity. This subject will be the central topic of this review. The authors also present recent results showing that, in hippocampal neurons, ROS/RNS, including ROS generated by iron through the Fenton reaction, stimulate ryanodine receptor-mediated calcium release, and how the resulting calcium signals activate the signaling cascades that lead to the transcription of genes known to participate in synaptic plasticity. They discuss the possible participation of ryanodine receptors jointly stimulated by calcium and ROS/RNS in the normal signaling cascades needed for synaptic plasticity, and how too much ROS production may contribute to neurodegeneration via excessive calcium release. In addition, the dual role of iron as a necessary, but potentially toxic, element for normal neuronal function is discussed.