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PMID:26276394

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Citation

Wu, M, Puddifoot, CA, Taylor, P and Joiner, WJ (2015) Mechanisms of inhibition and potentiation of α4β2 nicotinic acetylcholine receptors by members of the Ly6 protein family. J. Biol. Chem. 290:24509-18

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.

Links

PubMed PMC4591831 Online version:10.1074/jbc.M115.647248

Keywords

Allosteric Site; Animals; Antigens, Ly/metabolism; Biotinylation; Calcium/chemistry; Cell Membrane/metabolism; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins/metabolism; HEK293 Cells; Humans; Lipids/chemistry; Membrane Glycoproteins/metabolism; Mice; Neuropeptides/metabolism; Nicotine/chemistry; Nicotinic Agonists/pharmacology; Patch-Clamp Techniques; Protein Binding; Protein Transport; Receptors, Nicotinic/metabolism; Smoking/adverse effects; Type C Phospholipases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ACHA4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACHA4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8BLC3

F

Seeded From UniProt

complete

MOUSE:LY6E

enables

GO:0033130: acetylcholine receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY6E

enables

GO:0030550: acetylcholine receptor inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY6E

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LYPD1

enables

GO:0033130: acetylcholine receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LYPD1

enables

GO:0030550: acetylcholine receptor inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LYPD1

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LYPD1

acts_upstream_of_or_within

GO:1903077: negative regulation of protein localization to plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_transports_or_maintains_localization_of:(MGI:MGI:87888)

Seeded From UniProt

complete

MOUSE:LYPD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O70174

F

Seeded From UniProt

complete

MOUSE:LY66E

enables

GO:0033130: acetylcholine receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY66E

acts_upstream_of_or_within

GO:0002029: desensitization of G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LY66E

enables

GO:0030549: acetylcholine receptor activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY66E

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:LY66E

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACHB2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:LY6H

enables

GO:0033130: acetylcholine receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY6H

enables

GO:0030550: acetylcholine receptor inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY6H

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LY66D

enables

GO:0030550: acetylcholine receptor inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LY66D

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACHA4

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACHA4

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACHA4

part_of

GO:0005892: acetylcholine-gated channel complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACHB2

part_of

GO:0005892: acetylcholine-gated channel complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACHB2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ACHB2

acts_upstream_of_or_within

GO:0095500: acetylcholine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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