The responses of primary sensory neurons to subnanomolar and nanomolar ouabain concentrations, corresponding to the endogenous ouabain (EO) concentration, were studied. Atomic force microscopy (AFM) studies showed that exposure to EO led to an increase in neuron stiffness. Studies using local voltage clamping showed that ligand-receptor binding of EO with the Na,K-ATPase/Src complex decreased the effective charge of the activatory gate system of NaV1.8 channels. Furthermore, the EO-activated intracellular cascade in which the Na,K-ATPase/Src complex operates as a signal transducer was found to lead to a decrease in the fluorescence intensity of antibodies to NaV1.8 channels, as demonstrated by confocal laser scanning microscopy. These results suggest that EO, triggering the transduction function of the Na,K-ATPase/Src complex and the corresponding intracellular signal cascade, is able to modulate the expression of the SCN10A gene, which produces NaV1.8 channels, which are responsible for encoding nociceptive signals.
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P. Kometiani, J. Li, L. Gnudi, et al., “Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases,” J. Biol. Chem., 273, No. 24, 15249–15256 (1998).
Z. Xie and A. Askari, “Na+,K+-ATPase as a signal transducer,” Eur. J. Biochem., 269, 2434–2439 (2002).
B. V. Krylov, A. V. Derbenev, S. A. Podzorova, et al., “Morphine decreases the voltage sensitivity of slow sodium channels,” Ros. Fiziol. Zh., 85, No. 2, 225–236 (1999).
B. V. Krylov, I. V. Rogachevskii, T. N. Shelykh, and V. B. Plakhova, Frontiers in Pain Science, Vol. 1, New Nonopioid Analgesics: Understanding Molecular Mechanisms on the Basis of Patch-Clamp and Quantum Chemical Studies, Bentham Science Publishers, Sharjah, U.A.E. (2017).
V. A. Penniyaynen, V. B. Plakhova, I. V. Rogachevsky, et al., “Molecular mechanisms and signaling by comenic acid in nociceptive neurons influence the pathophysiology of neuropathic pain,” Pathophysiology, 26, No. 3–4, 245–252 (2019).
A. Kawamura, J. Guo, Y. Itagaki, et al., “On the structure of endogenous ouabain,” Proc. Natl. Acad. Sci. USA, 96, 6654–6659 (1999).
V. B. Plakhova, V. A. Penniyaynen, I. L. Yachnev, et al., “Src kinase controls signaling pathways in sensory neuron triggered by low-power infrared radiation,” Can. J. Physiol. Pharmacol., 97, No. 5, 400–406 (2019).
E. V. Lopatina, I. L. Yachnev, V. A. Penniyaynen, et al., “Modulation of signal-transducing function of neuronal membrane Na+,K+-ATPase by endogenous ouabain and low-power infrared radiation leads to pain relief,” Med. Chem., 8, No. 1, 33–39 (2012).
J. C. Chambers, J. Zhao, C. M. Terracciano, et al., “Genetic variation in SCN10A influences cardiac conduction,” Nat. Genet., 42, 149–152 (2010).
M. M. Khalisov, A. V. Ankudinov, V. A. Penniyaynen, et al., “Application of atomic force microscopy for investigation of Na+,K+-ATPase signal-transducing function,” Acta Physiological. Hung., 102, No. 2, 125–130 (2015).
T. G. Kuznetsova, M. N. Starodubtseva, N. I. Yegorenkov, et al., “Atomic force microscopy probing of cell elasticity,” Micron, 38, No. 8, 824–833 (2007).
N. Gavara, “A beginner’s guide to atomic force microscopy probing for cell mechanics,” Microsc. Res. Tech., 80, No. 1, 75–84 (2017).
I. N. Sneddon, “The relation between load and penetration in axisymmetric Boussinesq problem for a punch of arbitrary profile,” Int. J. Eng. Sci., 3, 47–57 (1965).
D. Nečas, and P. Klapetek, “Gwyddion. An open-source software for SPM data analysis,” Cent. Eur. J. Phys., 10, No. 1, 181–188 (2012).
O. P. Hamill, A. Marty, E. Neher, et al., “Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches,” Pflugers Arch., 391, No. 1, 85–100 (1981).
P. G. Kostyuk, O. A. Krishtal, and V. I. Pidoplichko, “Effect of internal fluoride and phosphate on membrane currents during intracellular dialysis of nerve cells,” Nature, 257, No. 5528, 691–693 (1975).
A. A. Elliott and J. R. Elliott, “Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia,” J. Physiol., 463, No. 4, 39–56 (1993).
Y. Osipchuk and E. Timin, “Electrical measurements on perfused cells,” in: Intracellular Perfusion of Excited Cells, P. G. Kostyuk and O. A. Krishtal (eds.), Wiley, New York (1984).
W. Almers, “Gating currents and charge movements in excitable membranes,” Rev. Physiol. Biochem. Pharmacol., 82, 97–190 (1978).
A. Askari, “The sodium pump and digitalis drugs: Dogmas and fallacies,” Pharmacol. Res. Perspect., 7, No. 4, e00505 (2019).
K. Hamada, H. Matsuura, M. Sanada, et al., “Properties of the Na+/K+ pump current in small neurons from adult rat dorsal root ganglia,” Br. J. Pharmacol., 138, No. 8, 1517–1527 (2003).
M. Mata, G. J. Siegel, V. Hieber, et al., “Differential distribution of Na,K-ATPase isoform mRNAs in the peripheral nervous system,” Brain Res., 546, 47–54 (1991).
M. Dobretsov, S. L. Hastings, T. J. Sims, et al., “Stretch receptor-associated expression of alpha 3 isoform of the Na+,K+-ATPase in rat peripheral nervous system,” Neuroscience, 116, No. 4, 1069–1080 (2003).
M. Dobretsov and J. R. Stimers, “Neuronal function and α3 isoform of the Na/K-ATPase,” Front. Biosci., 10, 2373–2396 (2005).
D. Romanovsky, A. E. Moseley, R. E. Mrak, et al., “Phylogenetic preservation of alpha3 Na+,K+-ATPase distribution in vertebrate peripheral nervous systems,” J. Comp. Neurol., 500, No. 6, 1106–1116 (2007).
D. Paul, R. D. Soignier, L. Minor, et al., “Regulation and pharmacological blockade of sodium-potassium ATPase: a novel pathway to neuropathy,” J. Neurol. Sci, 340, No. 1–2, 139–143 (2014).
J. M. Hamlyn, M. P. Blaustein, S. Bova, et al., “Identification and characterization of a ouabain-like compound from human plasma,” Proc. Natl. Acad. Sci. USA, 88, No. 14, 6259–6263 (1991).
J. M. Hamlyn and M. P. Blaustein, “Endogenous ouabain: recent advances and controversies,” Hypertension, 68, No. 3, 526–532 (2016).
H. Ogawa, F. Cornelius, A. Hirata, and C. Toyoshima, “Sequential substitution of K+ bound to Na+,K+-ATPase visualized by x-ray crystallography,” Nat. Commun., 6, 8004 (2015).
H. Deng, Z. Yang, Y. Li, G. Bao, et al., “Interactions of Na+,K+-ATPase and co-expressed delta-opioid receptor,” Neurosci. Res., 65, No. 3, 222–227 (2009).
A. K. Chang, P. E. Bijur, D. Esses, et al., “Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department. A randomized clinical trial,” JAMA, 318, No. 17, 1661–1667 (2017).
E. V. Lopatina and Yu. I. Polyakov, “The synthetic analgesic Anoceptin: results of preclinical and clinical studies,” Efferentnaya Ter., 17, No. 3, 79–81 (2011).
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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 106, No. 10, pp. 1289–1301, October, 2020.
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Penniyaynen, V.A., Khalisov, M.M., Podzorova, S.A. et al. Possible Antinociceptive Mechanisms Triggered by Nanomolar Ouabain Concentrations in Primary Sensory Neurons. Neurosci Behav Physi 51, 687–693 (2021). https://doi.org/10.1007/s11055-021-01122-1
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DOI: https://doi.org/10.1007/s11055-021-01122-1