What is it about?

Pannexin1 (Panx1) channels are expressed ubiquitously in human body and known to play an important role in various physiological and pathological conditions. Loss or gain of function mutations in human patients that alter Panx1 activity are associated with multiple disorders including intellectual disability and female infertility respectively. Past studies have reported that aberrant activation of Panx1 is associated with neurodegeneration in epilepsy, ischemia and Alzheimer’s disease. Therefore, understanding mechanisms behind Panx1 activation is important for developing therapeutics able to modulate Panx1 activity. In this study, we uncovered a distinct Panx1 channel activation mechanism that is initiated downstream of NMDA receptor (NMDAR) stimulation and regulated by binding of endoplasmic reticulum resident STIM proteins to Panx1. Using detailed structure-function characterization, electrophysiology, quantitative fluorescence imaging, binding assays, and reverse genetics, we demonstrate that STIM proteins interact physically with distinct region within N-terminal of Panx1 and this Panx1-STIM interaction leads to transition of Panx1 from small pore, primarily chloride permeable state, to large pore non-selective ion and solute permeating state. We report that large pore Panx1 activation can be blocked using a Panx1 specific antibody that binds to the N-terminal of Panx1 thereby inhibiting Panx1-STIM interaction. Importantly, this antibody does not affect the small pore Panx1 function thus it can be utilized as a modality specific blocker of Panx1 and a potential therapeutic strategy for Panx1-STIM implicated disorders.

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Why is it important?

Our study reveals a previously unrecognized key role for the N-terminal region of Panx1 in regulating the channel pore through its interaction with endoplasmic reticulum resident STIM proteins. This Panx1-STIM interaction occurs downstream of NMDA receptor (NMDAR) stimulation in neurons leading to large pore Panx1 activation. Using a N-terminal directed Panx1 specific antibody, we prove the importance of the N-terminal in regulating Panx1 currents downstream of NMDAR stimulation. This Panx1 function blocking antibody can be utilized as a modality specific blocker of Panx1-STIM interaction and help in understanding the physiological and pathological role of Panx1-STIM signaling in cell specific manner. Further, given the ubiquitous expression of both Panx1 and STIM proteins throughout the body, our findings open new avenues for understanding the modality-specific functions of Panx1.

Perspectives

Working on this manuscript has been a tremendous experience that required extreme hard work, patience and dedication. I would like to thank all the co-authors as without their ground work and support, my goal of publishing a first authored article would not be complete. To see the end result published in PNAS makes us all happy! I hope you enjoy reading the article and get inspired to come up with exciting discovery of your own.

Chetan Patil

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This page is a summary of: ER-resident STIM1/2 couples Ca 2+ entry by NMDA receptors to pannexin-1 activation, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2112870119.
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