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Abstract
α4β2 nicotinic acetylcholine receptors (nAChRs) are abundantly expressed throughout the central nervous system and are thought to be the primary target of nicotine, the main addictive substance in cigarette smoking. Understanding the mechanisms by which these receptors are regulated may assist in developing compounds to selectively interfere with nicotine addiction. Here we report previously unrecognized modulatory properties of members of the Ly6 protein family on α4β2 nAChRs. Using a FRET-based Ca(2+) flux assay, we found that the maximum response of α4β2 receptors to agonist was strongly inhibited by Ly6h and Lynx2 but potentiated by Ly6g6e. The mechanisms underlying these opposing effects appear to be fundamentally distinct. Receptor inhibition by Lynx2 was accompanied by suppression of α4β2 expression at the cell surface, even when assays were preceded by chronic exposure of cells to an established chaperone, nicotine. Receptor inhibition by Lynx2 also was resistant to pretreatment with extracellular phospholipase C, which cleaves lipid moieties like those that attach Ly6 proteins to the plasma membrane. In contrast, potentiation of α4β2 activity by Ly6g6e was readily reversible by pretreatment with phospholipase C. Potentiation was also accompanied by slowing of receptor desensitization and an increase in peak currents. Collectively our data support roles for Lynx2 and Ly6g6e in intracellular trafficking and allosteric potentiation of α4β2 nAChRs, respectively.
Highlights
Several Ly6 proteins inhibit ␣42 nicotinic acetylcholine receptors (nAChRs), but the underlying mechanisms and the properties of homologous modulatory proteins are not well understood
Several Ly6 Proteins Modulate ␣42 nAChR Activity—The best characterized members of the mammalian Ly6 family, Lynx1 and Lynx2, have both been shown to form complexes with ␣42 nAChRs in transfected HEK-293 cells and to modulate receptor activity when co-expressed in oocytes [33, 34], as well as in knock-out mice [34, 39]
Using a high-throughput calcium flux assay as an initial screen for functional modulators of ␣42 nAChRs, we show that multiple members of the Ly6 family can suppress ␣42 activity
Summary
Several Ly6 proteins inhibit ␣42 nAChRs, but the underlying mechanisms and the properties of homologous modulatory proteins are not well understood. ␣42 nAChRs are up-regulated during chronic exposure to nicotine, as measured by changes in binding sites for radiolabeled agonist at the cell surface [11,12,13,14,15] This effect is thought to contribute to nicotine’s addictive properties and possibly to its neuroprotective effects in Parkinson Disease (16 –22). The trafficking effect of Lynx is notable in that it suppresses up-regulation of ␣42 nAChRs following chronic exposure to nicotine In addition to this novel antagonistic property, we demonstrate that a previously uncharacterized Ly6 protein, Ly6g6e, potentiates ␣42 signaling by slowing receptor desensitization. Our data suggest that the Ly6 proteins and the mechanisms they employ to modulate ␣42 nAChRs are far more varied than previously recognized, with important implications for nicotine-mediated changes in nervous system function
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