Oxidative stress disruption of receptor-mediated calcium signaling mechanisms

Journal of Biomedical Science

Robert S Aronstam²  Yue-Wern Huang²  Adam L Martin²  Erica K Shannon²  Alexis G Martin²  Rhett A Reichard²  Joshua D Erickson²  Hsiu-Jen Wang²  Chiung-Tan Chang¹  Tso-Hao Tang¹ 

[1] Department of Life Science, National Taiwan Normal University, Taipei, Taiwan 116, Republic of China;Department of Biological Sciences, Missouri University of Science & Technology, 400 W 11th St, Rolla MO 65409, USA

关键词: Store-operated calcium entry (SOCE);    Phospholipase Cβ;    Oxidative stress;    Muscarinic acetylcholine receptor;    Inositol trisphosphate (IP3);    Calcium signaling;   

Others  :  823709
DOI  :  10.1186/1423-0127-20-48

 received in 2013-04-24, accepted in 2013-07-10,  发布年份 2013

【 摘 要 】

Background

Oxidative stress increases the cytosolic content of calcium in the cytoplasm through a combination of effects on calcium pumps, exchangers, channels and binding proteins. In this study, oxidative stress was produced by exposure to tert-butyl hydroperoxide (tBHP); cell viability was assessed using a dye reduction assay; receptor binding was characterized using [³H]N-methylscopolamine ([³H]MS); and cytosolic and luminal endoplasmic reticulum (ER) calcium concentrations ([Ca²⁺]_i and [Ca²⁺]_L, respectively) were measured by fluorescent imaging.

Results

Activation of M3 muscarinic receptors induced a biphasic increase in [Ca²⁺]_i: an initial, inositol trisphosphate (IP3)-mediated release of Ca²⁺ from endoplasmic reticulum (ER) stores followed by a sustained phase of Ca²⁺ entry (i.e., store-operated calcium entry; SOCE). Under non-cytotoxic conditions, tBHP increased resting [Ca²⁺]_i; a 90 minute exposure to tBHP (0.5-10 mM ) increased [Ca²⁺]_i from 26 to up to 127 nM and decreased [Ca²⁺]_L by 55%. The initial response to 10 μM carbamylcholine was depressed by tBHP in the absence, but not the presence, of extracellular calcium. SOCE, however, was depressed in both the presence and absence of extracellular calcium. Acute exposure to tBHP did not block calcium influx through open SOCE channels. Activation of SOCE following thapsigargin-induced depletion of ER calcium was depressed by tBHP exposure. In calcium-free media, tBHP depressed both SOCE and the extent of thapsigargin-induced release of Ca²⁺ from the ER. M3 receptor binding parameters (ligand affinity, guanine nucleotide sensitivity, allosteric modulation) were not affected by exposure to tBHP.

Conclusions

Oxidative stress induced by tBHP affected several aspects of M3 receptor signaling pathway in CHO cells, including resting [Ca²⁺]_i, [Ca²⁺]_L, IP3 receptor mediated release of calcium from the ER, and calcium entry through the SOCE. tBHP had little effect on M3 receptor binding or G protein coupling. Thus, oxidative stress affects multiple aspects of calcium homeostasis and calcium dependent signaling.

【 授权许可】

   
2013 Tang et al.; licensee BioMed Central Ltd.

【 图 表 】

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