C60 fullerenes disrupt cellular signalling leading to TRPC4 and TRPC6 channels opening by the activation of muscarinic receptors and G-proteins in small intestinal smooth muscles |
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| Affiliation: | 1. A.A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, 4 Bogomoletz Street, 01024 Kyiv, Ukraine;2. Institute of Pharmacology and Toxicology, National Academy of Medical Science, 14 Eugene Pottier Street, 03057 Kyiv, Ukraine;3. Zayed University, P.O. Box 144534, Abu Dhabi, United Arab Emirates;4. Taras Shevchenko National University of Kyiv, ESC “Institute of Biology and Medicine”, 64 Volodymyrska Street, 01601 Kyiv, Ukraine;5. Technical University of Ilmenau, Institute of Chemistry and Biotechnology, 25 Weimarer Street, 98693 Ilmenau, Germany;1. Brighton and Sussex Medical School, Brighton, UK;2. School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK;3. Centre for Stress and Age-Related Diseases, University of Brighton, Brighton, UK;1. Department of Life Science, Hanyang University, Seoul 04763, Republic of Korea;2. Natural Science Institute, Hanyang University, Seoul 04763, Republic of Korea |
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| Abstract: | The effect of water-soluble pristine C60 fullerene nanoparticles (C60NPs) on receptor-operated cation channels formed by TRPC4/C6 proteins in ileal smooth muscle cells was investigated for the first time. Activation of these channels subsequent to acetylcholine binding to the expressed in these cells M2 and M3 muscarinic receptors represents the key event in the parasympathetic control of gastrointestinal smooth muscle motility and cholinergic excitation-contraction coupling. Experiments were performed on single collagenase-dispersed mouse ileal myocytes using patch-clamp techniques with symmetrical 125 mM Cs+ solutions and [Ca2 +]i ‘clamped’ at 100 nM in order to isolate the muscarinic cation current (mICAT). The current was induced by intracellular infusion of 200 μM GTPγS, which activates G-proteins directly, i.e. bypassing the muscarinic receptors. C60NPs applied at 10− 6 M at peak response to activation of G-proteins caused mICAT inhibition by 47.0 ± 3.5% (n = 9). The inhibition developed rather slowly, with the time constant of 119 ± 16 s, was voltage-independent and irreversible. Thus, C60NPs are unlikely to cause any direct block of TRPC4/C6 channels; rather, they may accumulate in the membrane and disrupt G-protein signalling leading to mICAT generation. C60NPs may represent a novel class of biocompatible molecules for the treatment of disorders associated with enhanced gastrointestinal motility. |
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