Interleukin-6 prevents NMDA-induced neuronal Ca²⁺ overload via suppression of IP3 receptors

Abstract

Primary objective: The mechanism underlying interleukin-6 (IL-6) prevention of N-methyl-D-aspartate (NMDA)-induced neuronal Ca²⁺ overload was explored at the profile of Ca²⁺ channel receptors, including NMDA, inositol 1,4,5-trisphosphate and ryanodine receptors (NMDAR, IP3R and RyR, respectively).

Methods: Cerebellar granule neurons from 8-day-old rats were exposed to IL-6 (40 or 120 ng ml⁻¹) for 8 days and stimulated with NMDA (100 μM) for 15 or 30 minutes.

Results: NMDA evoked an acute and sustained enhancement of intracellular Ca²⁺ fluorescence intensity in the entire 15-minute NMDA application period. IL-6 prevented the acute and sustained intracellular Ca²⁺ elevation triggered by NMDA in a concentration-dependent manner. MK-801, an NMDAR antagonist, completely suppressed NMDA-evoked neuronal Ca²⁺ overload in the absence or presence of IL-6. IP3R antagonist 2-APB lessened NMDA-evoked acute and sustained cytosolic Ca²⁺ overload and IL-6 further reduced the acute 2-APB-dependent Ca²⁺ component. Dissimilarly, after RyR antagonist DAN treatment, NMDA still induced an acute and sustained elevation of intracellular Ca²⁺ levels, and the elevated Ca²⁺ was significantly suppressed by IL-6. Moreover, IL-6 down-regulated NMDAR1 and IP3R1 but did not alter RyR2 expression.

Conclusion: The present results suggest that IL-6 suppresses NMDA-induced neuronal Ca²⁺ overload by inhibiting NMDAR and IP3R activities.

• Cerebellar granule neurons
• interleukin-6
• intracellular Ca²⁺ overload
• inositol 1,4,5-trisphosphate receptor
• N-methyl-D-aspartate
• ryanodine receptor

Acknowledgements

We wish to thank Dr M. Kerry O’Banion, University of Rochester, for editing this manuscript.