Grant: Discovery Grants Program - Individual

The complex network that regulates communication between cells in mammalian tissues is responsible for the delicate balance between proliferation and differentiation of different cell types, as well as the cellular signalling through specialized channels that are required to orchestrate it. My research interests encompass the study of the channel-forming proteins called pannexins that are a family of three glycoproteins (genes: Panx1, Panx2 and Panx3). We have discovered that their primary function is to form large-pore membrane channels at the cell surface for the passage of ions and large metabolites involved in communication and signalling. However, they can also function intracellularly as calcium channels and through their interactions with key signalling networks like the Wnt pathway. My NSERC research program that started in 2015 with a Discovery Grant, is focused on Pannexin-2 (PANX2), which is the largest member of the family but the least characterized. PANX2 can form large-pore channels composed of several subunits of this protein and is expressed in many tissues of the central nervous system, skin, liver, gastrointestinal tract, kidneys, and testis. It has been shown to localize to the cell surface as well as to intracellular organelles in the interphase of the endoplasmic reticulum and mitochondria, participating in cell metabolism and mechanisms of cell death in neurons. We have shown that the PANX2 protein is post-translationally modified by addition of sugars as well as a substrate for caspase cleavage during programmed cell death of skin cells. These modifications can regulate the localization of PANX2 channels, their interactions with other pannexins and their channel function in the cells. In the current renewal, I propose that 1). The distribution and function of PANX2 channels are also regulated in the cell by alternative splicing of its transcripts, that can generate different isoforms of the PANX2 protein that is encoded in multiple exons of the gene. 2). Multiple post-translational modifications including phosphorylation and caspase cleavage can also regulate the activation of the channels and control their function in mammalian cells. 3). A deletion of the Panx2 gene in a mouse model will reveal the multiple functions that PANX2 has in mammalian tissues, and in particular its role in normal skin homeostasis. Impact: We are just beginning to uncover the cellular role of PANX2 channels and their interesting functional implications in mammalian physiology. These large-pore channels appear to be important in early stages of development in many tissues like skin and brain but need to be tightly regulated in the adult to avoid deleterious effects that result from uncontrolled channel opening at the surface or intracellularly. My NSERC research program will continue to elucidate the function and regulation of PANX2 channels at the gene, transcript, and protein level throughout mammalian development.