Knockdown of RTN1-C attenuates traumatic neuronal injury through regulating intracellular Ca2+ homeostasis.

Reticulons (RTNs) are a family of membrane-bound proteins that are dominantly localized to the endoplasmic reticulum (ER) membrane. RTN1-C is one member of RTNs abundantly expressed in the brain and has been shown to mediate neuronal injury in cerebral ischemia models. In the present study, we investigated the role of RTN1-C in an in vitro brain trauma model mimicked by traumatic neuronal injury (TNI) in primary cultured cortical neurons. TNI increased the expression of RTN1-C in cortical neurons but had no effect on RTN1-A and RTN1-B. Knockdown of RTN1-C with specific siRNA (Si-RTN1-C) significantly decreased cytotoxicity and apoptosis after TNI. The results of Ca2+ imaging showed that intracellular Ca2+ overload induced by TNI was attenuated by RTN1-C knockdown. Furthermore, the activation of metabotropic glutamate receptor 1 (mGluR1)-induced Ca2+ response was partially prevented by Si-RTN1-C transfection. We also evaluated the role of RTN1-C in store-operated Ca2+ entry (SOCE) in cortical neurons using the ER Ca2+ inducer thapsigargin (Tg). The results showed that knockdown of RTN1-C alleviated the SOCE-mediated Ca2+ influx and decreased the expression of stromal interactive molecule 1 (STIM1). In summary, the present study found that knockdown of RTN1-C protected neurons against TNI via preservation of intracellular Ca2+ homeostasis, which was associated with the inhibition of mGluR1-mediated ER Ca2+ release and suppression of STIM1-related SOCE. Thus, RTN1-C might represent a therapeutic target for traumatic brain injury (TBI) research.