Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System
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),...
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2020-02-01
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| Series: | Biomolecules |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mikhail G. Akimov |
| collection | DOAJ |
| description | 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<i> </i><i>californica</i>, 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 Ca<sup>2+</sup> rise, but inhibited the acetylcholine-evoked Ca<sup>2+</sup> rise with IC<sub>50</sub> 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 <i>K</i><sub>i </sub>=<i> </i>16.7 ± 1.5 μM and <i>αK</i><sub>i </sub>=<i> </i>51.4 ± 4.1 μM for AChE and <i>K</i><sub>i </sub>=<i> </i>70.5 ± 6.3 μM and <i>αK</i><sub>i </sub>=<i> </i>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. |
| first_indexed | 2024-12-11T07:24:11Z |
| format | Article |
| id | doaj.art-551c8934f5a34cb3af5aa30c2af613c4 |
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| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-11T07:24:11Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-551c8934f5a34cb3af5aa30c2af613c42022-12-22T01:16:00ZengMDPI AGBiomolecules2218-273X2020-02-0110228310.3390/biom10020283biom10020283Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling SystemMikhail G. Akimov0Denis S. Kudryavtsev1Elena V. Kryukova2Elena V. Fomina-Ageeva3Stanislav S. Zakharov4Natalia M. Gretskaya5Galina N. Zinchenko6Igor V. Serkov7Galina F. Makhaeva8Natalia P. Boltneva9Nadezhda V. Kovaleva10Olga G. Serebryakova11Sofya V. Lushchekina12Victor A. Palikov13Yulia Palikova14Igor A. Dyachenko15Igor E. Kasheverov16Victor I. Tsetlin17Vladimir V. Bezuglov18Department of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment medicinal and biological chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaDepartment of molecular neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaCholines 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<i> </i><i>californica</i>, 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 Ca<sup>2+</sup> rise, but inhibited the acetylcholine-evoked Ca<sup>2+</sup> rise with IC<sub>50</sub> 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 <i>K</i><sub>i </sub>=<i> </i>16.7 ± 1.5 μM and <i>αK</i><sub>i </sub>=<i> </i>51.4 ± 4.1 μM for AChE and <i>K</i><sub>i </sub>=<i> </i>70.5 ± 6.3 μM and <i>αK</i><sub>i </sub>=<i> </i>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.https://www.mdpi.com/2218-273X/10/2/283nachrarachidonoylcholineoleoylcholineacylcholinesacetylcholinesterase |
| spellingShingle | 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 Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System Biomolecules nachr arachidonoylcholine oleoylcholine acylcholines acetylcholinesterase |
| title | Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System |
| title_full | Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System |
| title_fullStr | Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System |
| title_full_unstemmed | Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System |
| title_short | Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System |
| title_sort | arachidonoylcholine and other unsaturated long chain acylcholines are endogenous modulators of the acetylcholine signaling system |
| topic | nachr arachidonoylcholine oleoylcholine acylcholines acetylcholinesterase |
| url | https://www.mdpi.com/2218-273X/10/2/283 |
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