Regulation of neuronal development and function by ROS

Regulation of neuronal development and function by ROS

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The importance of calcium?

The mechanisms by which physiological levels of ROS support neurite outgrowth and axon specification appear to involve release of calcium from intracellular stores, a potent second messenger regulating cytoskeletal organisation and dynamics (reviewed in 35, 36).  Short respiratory bursts of NADPH oxidase‐generated ROS promote calcium release by redox modification of ryanodine (RyRs) and inositol‐3‐phosphate receptors (IP3Rs). These in turn lead to increased expression of Rac1, an activator of the NOX2 complex, thus generating a positive feedback loop that can convert initially transient ROS bursts into sustained ROS activation and high levels of intracellular calcium 34; (Fig. 1).

H₂O₂ also modifies RyRs and IP3Rs triggering release of calcium from internal stores in the ER. (4) Changes in intracellular calcium modify activities of cytoskeletal regulatory proteins, directly or indirectly, e.g. via the regulation of Calcium/calmodulin‐dependent kinase II (CamKII) or the phosphatase calcineurin or activation of the protease calpain. Elevated calcium levels also lead to expression of the cytoskeletal and NADPH oxidase regulator Rac1, thus generating a positive feedback loop that can amplify and sustain transient respiratory bursts 34.

NADPH oxidase activity is subject to complex regulatory pathways, of which many are associated with neuronal activation, such as elevated intracellular calcium levels, Protein kinases C and A, as well as calmodulin and calcium/calmodulin‐dependent kinase II (CamKII) 34, 56, 95–98.

Interestingly, in cerebellar Purkinje neurons superoxide is required for LTD, although in these cells synaptic depression (as opposed to potentiation) requires elevated intracellular calcium concentration 113.