Fingolimod inhibits glutamate release through activation of S1P1 receptors and the G protein βγ subunit-dependent pathway in rat cerebrocortical nerve terminals.

Che Chuan Wang, Jinn Rung Kuo, Su Jane Wang

Neuropharmacology 2021 Mar 01

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Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator approved for treating multiple sclerosis, is reported to prevent excitotoxic insult. Because excessive glutamate release is a major cause of neuronal damage in various neurological disorders, the effect of fingolimod on glutamate release in rat cerebrocortical nerve terminals (synaptosomes) was investigated in the current study. Fingolimod decreased 4-aminopyridine (4-AP)-stimulated glutamate release and calcium concentration elevation. Fingolimod-mediated inhibition of 4-AP-induced glutamate release was dependent on extracellular calcium, persisted in the presence of the glutamate transporter inhibitor DL-TBOA or intracellular Ca2+-releasing inhibitors dantrolene and CGP37157, and was prevented by blocking vesicular transporters or N- and P/Q-type channels. Western blot and immunocytochemical analysis revealed the presence of S1P1 receptor proteins in presynaptic terminals. Fingolimod-mediated inhibition of 4-AP-induced glutamate release was also abolished by the sphingosine kinase inhibitor DMS, selective S1P1 receptor antagonist W146, Gi/o protein inhibitor pertussis toxin, and G protein βγ subunit inhibitor gallein; however, it was unaffected by the adenylyl cyclase inhibitor SQ22536, protein kinase A inhibitor H89, and phospholipase C inhibitor U73122. These data indicate that fingolimod decreases glutamate release from rat cerebrocortical synaptosomes by suppressing N- and P/Q-type Ca2+ channel activity; additionally, the activation of presynaptic S1P1 receptors and the G protein βγ subunit participates in achieving the effect. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Che Chuan Wang, Jinn Rung Kuo, Su Jane Wang. Fingolimod inhibits glutamate release through activation of S1P1 receptors and the G protein βγ subunit-dependent pathway in rat cerebrocortical nerve terminals. Neuropharmacology. 2021 Mar 01;185:108451