Ukr.Biochem.J. 2023; Volume 95, Issue 2, Mar-Apr, pp. 24-32

doi: https://doi.org/10.15407/ubj95.02.024

Choline derivatives as natural ligands of mitochondrial nicotinic acetylcholine receptors

13.06.2023   Uncategorized   No comments

O. Lykhmus, M. Izmailov, M. Skok*

Department of Molecular Immunology, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
*e-mail: skok@biochem.kiev.ua

Received: 16 March 2023; Revised: 28 April 2023;
Accepted: 05 June 2023; Available on-line: 20 June 2023

Nicotinic acetylcholine receptors (nAChRs) regulate mitochondria-driven apoptosis; however, their intracellular ligands are unknown. In the present paper, we show that choline and its derivatives (phosphocholine (PC), L-α-glycerophosphocholine (G-PC) and 1-palmitoyl-sn-glycero-3-phosphocholine (P-GPC)) dose-dependently influence cytochrome c release from isolated mouse liver mitochondria. Choline inhibited Ca2+-stimulated cytochrome c release, while PC attenuated wortmannin-induced cytochrome c release. Small doses of G-PC and P-GPC (up to 0.1 µM) were protective against either Ca2+ or wortmannin, while larger doses (up to 1 µM) stimulated cytochrome c release by themselves. Choline and PC disrupted interaction of VDAC1, Bax and Bcl-2 with mitochondrial α7 nAChRs and favored their interaction with α9 nAChR subunits. It is concluded that choline metabolites can regulate apoptosis by affecting mitochondrial nAChRs.

Keywords: , , , , ,

References:

  1. Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G, Lazaridis K, Sideri A, Zouridakis M, Tzartos SJ. Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J. 2007;274(15):3799-3845. PubMed, CrossRef
  2. Kawashima K, Fujii T. Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci. 2008;106(2):167-173. PubMed, CrossRef
  3. de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol. 2007;151(7):915-929. PubMed, PubMedCentral, CrossRef
  4. Skok M. Mitochondrial nicotinic acetylcholine receptors: Mechanisms of functioning and biological significance. Int J Biochem Cell Biol. 2022;143:106138. PubMed, CrossRef
  5. Gergalova G, Lykhmus O, Komisarenko S, Skok M. α7 Nicotinic acetylcholine receptors control cytochrome c release from isolated mitochondria through kinase-mediated pathways. Int J Biochem Cell Biol. 2014;49:26-31. PubMed, CrossRef
  6. Zakrzewicz A, Richter K, Zakrzewicz D, Siebers K, Damm J, Agné A, Hecker A, McIntosh JM, Chamulitrat W, Krasteva-Christ G, Manzini I, Tikkanen R, Padberg W, Janciauskiene S, Grau V. SLPI Inhibits ATP-Mediated Maturation of IL-1β in Human Monocytic Leukocytes: A Novel Function of an Old Player. Front Immunol. 2019;10:664. PubMed, PubMedCentral, CrossRef
  7. McIntosh JM, Plazas PV, Watkins M, Gomez-Casati ME, Olivera BM, Elgoyhen AB. A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors. J Biol Chem. 2005;280(34):30107-30112. PubMed, CrossRef
  8. Skok MV, Voitenko LP, Voitenko SV, Lykhmus EY, Kalashnik EN, Litvin TI, Tzartos SJ, Skok VI. Alpha subunit composition of nicotinic acetylcholine receptors in the rat autonomic ganglia neurons as determined with subunit-specific anti-alpha(181-192) peptide antibodies. Neuroscience. 1999;93(4):1427-1436. PubMed, CrossRef
  9. Koval L, Lykhmus O, Zhmak M, Khruschov A, Tsetlin V, Magrini E, Viola A, Chernyavsky F, Qian J, Grando S, Komisarenko S, Skok M. Differential involvement of α4β2, α7 and α9α10 nicotinic acetylcholine receptors in B lymphocyte activation in vitro. Int J Biochem Cell Biol. 2011;43(4):516-524. PubMed, CrossRef
  10. Sottocasa GL, Kuylenstierna B, Ernster L, Bergstrand AJ. An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol. 1967;32(2):415-438. PubMed, PubMedCentral, CrossRef
  11. Uspenska K, Lykhmus O, Gergalova G, Chernyshov V, Arias HR, Komisarenko S, Skok M. Nicotine facilitates nicotinic acetylcholine receptor targeting to mitochondria but makes them less susceptible to selective ligands. Neurosci Lett. 2017;656:43-50. PubMed, CrossRef
  12. Wonnacott S. Nicotinic ACh receptors. In: Tocris Bioscience Scientific Review Series, Tocris Cookson, Ltd, 2014; 1-31.
  13. Uspenska K, Lykhmus O, Obolenskaya M, Pons S, Maskos U, Komisarenko S, Skok M. Mitochondrial nicotinic acetylcholine receptors support liver cells viability after partial hepatectomy. Front Pharmacol. 2018;9:626.
    PubMed, PubMedCentral, CrossRef
  14. Kalashnyk O, Lykhmus O, Uspenska K, Izmailov M, Komisarenko S, Skok M. Mitochondrial α7 nicotinic acetylcholine receptors are displaced from complexes with VDAC1 to form complexes with Bax upon apoptosis induction. Int J Biochem Cell Biol. 2020;129:105879.
    PubMed, CrossRef
  15. Omelchenko DM, Kalashnyk OM, Koval LM, Skok MV, Komisarenko SV. Analysis of signaling pathways activated by nicotinic acetylcholine receptors in B-lymphocyte-derived cells. Ukr Biokhim Zhurn. 2009;81(1):59-66.(In Ukrainian). PubMed
  16. Dajas-Bailador F, Wonnacott S. Nicotinic acetylcholine receptors and the regulation of neuronal signalling. Trends Pharmacol Sci. 2004;25(6):317-324. PubMed, CrossRef
  17. Parada E, Egea J, Romero A, del Barrio L, García AG, López MG. Poststress treatment with PNU282987 can rescue SH-SY5Y cells undergoing apoptosis via α7 nicotinic receptors linked to a Jak2/Akt/HO-1 signaling pathway. Free Radic Biol Med. 2010;49(11):1815-1821. PubMed, CrossRef
  18. Miura T, Tanno M, Sato T. Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis. Cardiovasc Res. 2010;88(1):7-15. PubMed, CrossRef
  19. Mookherjee P, Quintanilla R, Roh MS, Zmijewska AA, Jope RS, Johnson GVW. Mitochondrial-targeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death. J Cell Biochem. 2007;102(1):196-210. PubMed, PubMedCentral, CrossRef
  20. Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, Trent JO, Chesney J. A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene. 2011;30(30):3370-3380. PubMed, PubMedCentral, CrossRef
  21. Sonkar K, Ayyappan V, Tressler CM, Adelaja O, Cai R, Cheng M, Glunde K. Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer. NMR Biomed. 2019;32(10):e4112. PubMed, PubMedCentral, CrossRef
  22. Pucci S, Fasoli F, Moretti M, Benfante R, Di Lascio S, Viani P, Antonio D, Gordon TJ, McIntosh M, Zoli M, Clementi F, Gotti C. Choline and nicotine increase glioblastoma cell proliferation by binding and activating α7- and α9- containing nicotinic receptors. Pharmacol Res. 2021;163:105336. PubMed, CrossRef
  23. Ridgway ND. The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. Crit Rev Biochem Mol Biol. 2013;48(1):20-38. PubMed, CrossRef
  24. Righi V, Roda JM, Paz J, Mucci A, Tugnoli V, Rodriguez-Tarduchy G, Barrios L, Schenetti L, Cerdan S, Garcia-Martin ML. 1H HR-MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas. NMR Biomed. 2009;22(6):629-637. PubMed, CrossRef
  25. Pucci S, Zoli M, Clementi F, Gotti C. α9-Containing Nicotinic Receptors in Cancer. Front Cell Neurosci. 2022;15:805123. PubMed, PubMedCentral, CrossRef
  26. Richter K, Mathes V, Fronius M, Althaus M, Hecker A, Krasteva-Christ G, Padberg W, Hone AJ, McIntosh JM, Zakrzewicz A, Grau V. Phosphocholine – an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors. Sci Rep. 2016;6:28660. PubMed, PubMedCentral, CrossRef
  27. Ball JC. Binding of quaternary ammonium salts to acetylcholine receptors: possible chemical warfare nerve agents. Mil Med Sci Lett. 2013;82(1):2-24. CrossRef
  28. Mishra NC, Rir-sima-ah J, Boyd RT, Singh SP, Gundavarapu S, Langley RJ, Razani-Boroujerdi S, Sopori ML. Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors. J Immunol. 2010;185(1):588-596. PubMed, PubMedCentral, CrossRef
  29. Lykhmus O, Voytenko LP, Lips KS, Bergen I, Krasteva-Christ G, Vetter DE, Kummer W, Skok M. Nicotinic Acetylcholine Receptor α9 and α10 Subunits Are Expressed in the Brain of Mice. Front Cell Neurosci. 2017;11:282. PubMed, PubMedCentral, CrossRef
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