Adenosine A2B receptors inhibit K+ currents and cell differentiation in cultured oligodendrocyte precursor cells and modulate sphingosine-1-phosphate signaling pathway

被引：19

作者：

Coppi, Elisabetta ^{[1
]}

Cherchi, Federica ^{[1
]}

Fusco, Irene ^{[1
]}

Dettori, Ilaria ^{[1
]}

Gaviano, Lisa ^{[1
]}

Magni, Giada ^{[2
]}

Catarzi, Daniela ^{[3
]}

Colotta, Vittoria ^{[3
]}

Varano, Flavia ^{[3
]}

Rossi, Francesca ^{[2
]}

Bernacchioni, Caterina ^{[4
]}

Donati, Chiara ^{[4
]}

Bruni, Paola ^{[4
]}

Pedata, Felicita ^{[1
]}

Cencetti, Francesca ^{[4
]}

Pugliese, Anna Maria ^{[1
]}

机构：

[1] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth NEURO, Sect Pharmacol & Toxicol, Florence, Italy

[2] CNR, Ist Fis Applicata, Via Madonna del Piano 10, I-50019 Florence, Italy

[3] Univ Florence, Dept NEUROFARBA, Sect Pharmaceut & Nutraceut Sci, Florence, Italy

[4] Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy

来源：

BIOCHEMICAL PHARMACOLOGY | 2020年 / 177卷

关键词：

A(2B) adenosine receptors; Sphingosine-1-phosphate; OPC differentiation; Remyelination; K+ currents; SPHINGOSINE; 1-PHOSPHATE; MYOGENIC DIFFERENTIATION; LYSOPHOSPHATIDIC ACID; INTERNATIONAL-UNION; LINEAGE PROGRESSION; POTASSIUM CURRENTS; ION CHANNELS; PROLIFERATION; FTY720; ACTIVATION;

D O I：

10.1016/j.bcp.2020.113956

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Oligodendrocytes are the only myelinating cells in the brain and differentiate from their progenitors (OPCs) throughout adult life. However, this process fails in demyelinating pathologies. Adenosine is emerging as an important player in OPC differentiation and we recently demonstrated that adenosine A(2A) receptors inhibit cell maturation by reducing voltage-dependent K+ currents. No data are available to date about the A(2B) receptor (A(2B)R) subtype. The bioactive lipid mediator sphingosine-1-phosphate (S1P) and its receptors (S1P(1-5)) are also crucial modulators of OPC development. An interaction between this pathway and the A(2B)R is reported in peripheral cells. We studied the role of A(2B)Rs in modulating K+ currents and cell differentiation in OPC cultures and we investigated a possible interplay with SIP signaling. Our data indicate that the A(2B)R agonist BAY60-6583 and its new analogue P453 inhibit K+ currents in cultured OPC and the effect was prevented by the A(2B)R antagonist MRS1706, by K+ channel blockers and was differently modulated by the S1P analogue FTY720-P. An acute (10 min) exposure of OPCs to BAY60-6583 also increased the phosphorylated form of sphingosine kinase 1 (SphK1). A chronic (7 days) treatment with the same agonist decreased OPC differentiation whereas SphK1/2 inhibition exerted the opposite effect. Furthermore, A(2B)R was overexpressed during OPC differentiation, an effect prevented by the pan SphK1/2 inhibitor VPC69047. Finally, A(2B)R silenced cells showed increased cell maturation, decreased SphK1 expression and enhanced S1P lyase levels. We conclude that A(2B)Rs inhibit K currents and cell differentiation and positively modulate S1P synthesis in cultured OPCs.

引用

页数：16

共 66 条

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