Abstract
Pannexin 1 (Panx1) channels are widely recognized for their role in ATP release, and as follows, their function is closely tied to that of ATP-activated P2X7 purinergic receptors (P2X7Rs). Our recent work has shown that extracellular ATP induces clustering of Panx1 with P2X7Rs and their subsequent internalization through a non-canonical cholesterol-dependent mechanism. In other words, we have demonstrated that extracellular ATP levels can regulate the cell surface expression of Panx1. Here we discuss two situations in which we hypothesize that ATP modulation of Panx1 surface expression could be relevant for central nervous system function. The first scenario involves the development of new neurons in the ventricular zone. We propose that ATP-induced Panx1 endocytosis could play an important role in regulating the balance of cell proliferation, survival, and differentiation within this neurogenic niche in the healthy brain. The second scenario relates to the spinal cord, in which we posit that an impairment of ATP-induced Panx1 endocytosis could contribute to pathological neuroplasticity. Together, the discussion of these hypotheses serves to highlight important outstanding questions regarding the interplay between extracellular ATP, Panx1, and P2X7Rs in the nervous system in health and disease.
Highlights
Recent work from our lab demonstrated that an elevation in extracellular ATP triggers clustering of P2X7Rs and Pannexin 1 (Panx1) leading to endocytosis to intracellular membranes
Adding further complexity to P2X7R-Panx1 crosstalk, we recently demonstrated that elevation of extracellular ATP leads to Panx1 internalization (Boyce et al, 2015; Boyce and Swayne, 2017), thereby reducing Panx1 surface expression
We recently demonstrated that selective deletion of Panx1 in ventricular zone neural precursor cell (NPC) led to their loss over time (WickiStordeur et al, 2016)
Summary
Recent work from our lab demonstrated that an elevation in extracellular ATP triggers clustering of P2X7Rs and Panx leading to endocytosis to intracellular membranes This regulation of Panx surface expression by extracellular ATP has important implications for several physiological and pathophysiological scenarios within the nervous system. We present hypotheses describing two scenarios for regulation of cell surface Panx expression through putative P2X7R-crosstalk. These include (1) regulation of neural precursor cell (NPC) development within the ventricular zone, and (2) chronic pain and opioid dependence in the spinal cord.
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