Disruption of Muscarinic Receptor Mediated Signal Transduction by Oxidative Stress

The ability of a series of metal oxide nanoparticles (20 - 60 nm) to alter muscarinic receptor signaling was studied in cells with the human M3 muscarinic acetylcholine receptor. Activation of M3 receptors induced a biphasic increase in [Ca2+]i: an initial, 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). The different particles had multiple effects on calcium metabolism and muscarinic signaling: resting calcium concentration was increased and SOCE entry was decreased among other effects. Only ZnO and CuO particles consistently increased resting [Ca2+]i. SOCE was depressed by several metal oxide particles in disparate degrees. ZnO depressed most aspects of calcium signaling in response to muscarinic stimulation. The effect of SOCE depression did not correlate highly with cytotoxicity. The present findings raise the possibility that nanoparticle-induced cytotoxicity and nanoparticle-induced SOCE depression have different mechanisms of action