title: Mitochondria express several nicotinic acetylcholine receptor subtypes to control various pathways of apoptosis induction.
abstract: Nicotinic acetylcholine receptors control survival, proliferation and cytokine release in non-excitable cells. Previously we reported that α7 nicotinic receptors were present in the outer membranes of mouse liver mitochondria to regulate mitochondrial pore formation and cytochrome c release. Here we used a wide spectrum of nicotinic receptor subunit-specific antibodies to show that mitochondria express several nicotinic receptor subtypes in a tissue-specific manner: brain and liver mitochondria contain α7β2, α4β2 and less α3β2 nicotinic receptors, while mitochondria from the lung express preferentially α3β4 receptor subtype; all of them are non-covalently connected to voltage-dependent anion channels and control cytochrome c release. By using selective ligands of different nicotinic receptor subtypes (acetylcholine (1 μM) or dihydro-β-erythroidine (1 μM) for α4β2), conotoxin MII (1 nM) for α3β2, MLA (50 nM) for α7β2 and acetylcholine (10 μM) for all subtypes) and apoptogenic agents triggering different mitochondrial signaling pathways (1 μM wortmannin, 90 μM Ca(2+) or 0.5 mM H₂O₂) it was found that α7β2 receptors affect mainly PI₃K/Akt pathway, while α3β2 and α4β2 nAChRs also significantly influence CaKMII- and Src-dependent pathways. It is concluded that cholinergic regulation in mitochondria is realized through multiple nicotinic receptor subtypes, which control various pathways inducing mitochondrial type of apoptosis.
authors.affiliation: Palladin Institute of Biochemistry, 9, Leontovicha str., 01601 Kyiv, Ukraine.
authors.forename: Olena
authors.initials: O
authors.lastname: Lykhmus
authors.affiliation: Palladin Institute of Biochemistry, 9, Leontovicha str., 01601 Kyiv, Ukraine.
authors.forename: Galyna
authors.initials: G
authors.lastname: Gergalova
authors.affiliation: Palladin Institute of Biochemistry, 9, Leontovicha str., 01601 Kyiv, Ukraine.
authors.forename: Lyudmyla
authors.initials: L
authors.lastname: Koval
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10, Miklukho-Maklaya str., 117997 Moscow, Russian Federation.
authors.forename: Maxim
authors.initials: M
authors.lastname: Zhmak
authors.affiliation: Palladin Institute of Biochemistry, 9, Leontovicha str., 01601 Kyiv, Ukraine.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Komisarenko
authors.affiliation: Palladin Institute of Biochemistry, 9, Leontovicha str., 01601 Kyiv, Ukraine. Electronic address: skok@biochem.kiev.ua.
authors.forename: Maryna
authors.initials: M
authors.lastname: Skok
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D021122:Protein Subunits; D011978:Receptors, Nicotinic; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D000109:Acetylcholine
keywords: Apoptosis; Cytochrome c; Mitochondria; Mitochondrial kinases; Nicotinic acetylcholine receptor