Control of Intracellular Calcium Signaling as a Neuroprotective Strategy

Abstract

Both acute and chronic degenerative diseases of the nervous system reduce the viability and function of neurons through changes in intracellular calcium signaling. In particular, pathological increases in the intracellular calcium concentration promote such pathogenesis. Disease involvement of numerous regulators of intracellular calcium signaling located on the plasma membrane and intracellular organelles has been documented. Diverse groups of chemical compounds targeting ion channels, G-protein coupled receptors, pumps and enzymes have been identified as potential neuroprotectants. The present review summarizes the discovery, mechanisms and biological activity of neuroprotective molecules targeting proteins that control intracellular calcium signaling to preserve or restore structure and function of the nervous system. Disease relevance, clinical applications and new technologies for the identification of such molecules are being discussed.

Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons

“…Our findings underscore the notion that the cellular pathways activated by increased [Ca 2+ ] i are potential causative factors underlying many age-related disorders in the SCN, similar to other brain regions (Duncan et al, 2010;Foster, 2007;Hermes et al, 2010;Kumar et al, 2009). Moreover, restoring baseline [Ca 2+ ] i levels in aged SCN neurons may help alleviate many age-related problems (Disterhoft and Oh, 2006;Duncan et al, 2010).…”

Differential subcellular Ca2+ signaling in a highly specialized subpopulation of astrocytes

“…We have previously reported the selective up-regulation of IP 3 R2 under conditions of oxidative stress in neuronal HT-22 cells (Kaja, et al, 2011) indicating that the high physiological relevance of IP 3 R2 for normal ONHA Ca 2+ signaling could become even more pronounced under disease conditions associated with oxidative stress. Of particular relevance, aberrant Ca 2+ signaling has been described both in preclinical glaucoma models and glaucoma patients (reviewed in Crish and Calkins, 2011) and is considered a viable target for neuroprotection (Duncan, et al, 2010, Payne, et al, 2014, Payne, et al, 2013). …”

“…Cellular Ca 2+ homeostasis is tightly regulated and changes in the intracellular Ca 2+ concentration control important physiological processes, especially in cell types such as neurons where they include neurotransmitter release and gene expression (Duncan, et al, 2010). In neurons and brain astrocytes alike, these changes are mediated by either Ca 2+ influx through (voltage-gated) plasma membrane Ca 2+ channels (VGCCs) or release from intracellular Ca 2+ stores (Beck, et al, 2004, Gleichmann and Mattson, 2011, Nag, 2011, Venance, et al, 1997, Worley, et al, 1987).…”

“…Genetic, age-related and pathological changes in Ca 2+ signaling underlie a significant number of neurological and neurodegenerative disorders, including glaucoma (Duncan, et al, 2010, Gleichmann and Mattson, 2011, Payne, et al, 2013). Targeting aberrant Ca 2+ signaling in neurodegeneration is widely considered a promising strategy and the target of significant drug development efforts (Payne, et al, 2013), and identifying the molecular determinants of intracellular Ca 2+ signaling in ONHAs is critically important for drug discovery for glaucoma and related disorders affecting the ON and ON head.…”

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

“…Using single channel recordings of IP3Rs it was observed that expression of mutant PS1 and PS2 is associated with an apparent sensitization of the IP3R channel to IP3, resulting in enhanced channel gating (94). IP3R levels are reduced in the brains of patients with AD and correlates with the increased occurrence of amyloid plaques and neurofibrillary tangles (95, 96). Further, IP3R activity is altered in neurons cultured from AD mouse models (97–99).…”