Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System
Mikhail G. Akimov,
Denis S. Kudryavtsev,
Elena V. Kryukova,
Elena V. Fomina-Ageeva,
Stanislav S. Zakharov,
Natalia M. Gretskaya,
Galina N. Zinchenko,
Igor V. Serkov,
Galina F. Makhaeva,
Natalia P. Boltneva,
Nadezhda V. Kovaleva,
Olga G. Serebryakova,
Sofya V. Lushchekina,
Victor A. Palikov,
Yulia Palikova,
Igor A. Dyachenko,
Igor E. Kasheverov,
Victor I. Tsetlin,
Vladimir V. Bezuglov
Affiliations
Mikhail G. Akimov
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Denis S. Kudryavtsev
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Elena V. Kryukova
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Elena V. Fomina-Ageeva
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Stanislav S. Zakharov
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Natalia M. Gretskaya
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Galina N. Zinchenko
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Igor V. Serkov
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Galina F. Makhaeva
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Natalia P. Boltneva
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Nadezhda V. Kovaleva
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Olga G. Serebryakova
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Sofya V. Lushchekina
Department medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
Victor A. Palikov
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Yulia Palikova
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Igor A. Dyachenko
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Igor E. Kasheverov
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Victor I. Tsetlin
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Vladimir V. Bezuglov
Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both α7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica, as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing α7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca2+ rise, but inhibited the acetylcholine-evoked Ca2+ rise with IC50 9 to 12 μM. In the A549 lung cancer cells, where α7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 ± 1.5 μM and αKi = 51.4 ± 4.1 μM for AChE and Ki = 70.5 ± 6.3 μM and αKi = 214 ± 17 μM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system.
