Abstract
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.
Highlights
Pentameric ligand-gated ion channels are essential determinants of synaptic transmission, and the targets of many allosteric modulators including general anesthetics and anti-epileptics (Corringer et al, 2012)
After optimizing native mass spectrometry (MS) for Erwinia ligand-gated ion channel (ELIC), we demonstrate that phospholipids directly bind to ELIC, with more binding observed for the anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) compared to zwitterionic phospholipids, 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE), and POPC
Recent structural and computational evidence suggests that lipids bind to Pentameric ligand-gated ion channels (pLGICs) at specific sites within the transmembrane domain (TMD) (Prevost et al, 2012; Basak et al, 2017; Althoff et al, 2014; Laverty et al, 2019; Carswell et al, 2015b)
Summary
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and the targets of many allosteric modulators including general anesthetics and anti-epileptics (Corringer et al, 2012). These ion channels are embedded in a heterogeneous and dynamic lipid environment (Allen et al, 2007), and the presence of specific lipids fine-tunes the function of pLGICs and may play a role in regulating neuronal excitability and drug sensitivity (Baenziger et al, 2015; Rosenhouse-Dantsker et al, 2012; Evers et al, 1986).
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