New Principal Investigators 12

The endoplasmic reticulum (ER) is essential for the proper folding, posttranslational modification, and transport of newly synthesized proteins. Moreover, the ER plays an important role in intracellular Ca²⁺ signaling and homeostasis. Many neurodegenerative diseases (e.g. Parkinson’s, Huntington’s and Alzheimer’s disease) are associated with an accumulation of misfolded proteins which disrupts ER function and induces ER stress. The resulting ER stress leads to Ca²⁺ dysregulation and cell death by apoptotic means. The precise mechanisms contributing to Ca²⁺ dysregulation downstream of ER stress are not known, but recent evidence suggests that plasma membrane channels could contribute to the increased ionic influx that triggers cell death. The pannexin channel, a large-pore channel soluble to solutes of up to 1 kDa, has been implicated in neuronal cell death and is a suitable candidate for triggering ionic influx. The mechanisms contributing to pannexin activation are poorly characterized; however, we now present evidence suggesting that ER stress promotes pannexin channel activation. Moreover, we have identified a specific ER-resident protein, the stromal interaction molecule (STIM), as a key signaling component promoting pannexin activation during ER stress. The findings described provide mechanistic insight as to how the ER communicates with surface expressed pannexin channels under duress. Given numerous studies implicating ER stress in neurodegeneration the mechanisms identified here may have broad implications for these diseases.