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PMID:21399631

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Citation

Cremona, ML, Matthies, HJ, Pau, K, Bowton, E, Speed, N, Lute, BJ, Anderson, M, Sen, N, Robertson, SD, Vaughan, RA, Rothman, JE, Galli, A, Javitch, JA and Yamamoto, A (2011) Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat. Neurosci. 14:469-77

Abstract

Plasmalemmal neurotransmitter transporters (NTTs) regulate the level of neurotransmitters, such as dopamine (DA) and glutamate, after their release at brain synapses. Stimuli including protein kinase C (PKC) activation can lead to the internalization of some NTTs and a reduction in neurotransmitter clearance capacity. We found that the protein Flotillin-1 (Flot1), also known as Reggie-2, was required for PKC-regulated internalization of members of two different NTT families, the DA transporter (DAT) and the glial glutamate transporter EAAT2, and we identified a conserved serine residue in Flot1 that is essential for transporter internalization. Further analysis revealed that Flot1 was also required to localize DAT within plasma membrane microdomains in stable cell lines, and was essential for amphetamine-induced reverse transport of DA in neurons but not for DA uptake. In sum, our findings provide evidence for a critical role of Flot1-enriched membrane microdomains in PKC-triggered DAT endocytosis and the actions of amphetamine.

Links

PubMed PMC3066276 Online version:10.1038/nn.2781

Keywords

Animals; Dopamine Plasma Membrane Transport Proteins/metabolism; Endocytosis/drug effects; Endocytosis/physiology; Excitatory Amino Acid Transporter 2/metabolism; Excitatory Amino Acid Transporter 2/physiology; HEK293 Cells; HeLa Cells; Humans; Membrane Microdomains/metabolism; Membrane Proteins/physiology; Mice; Neuroglia/metabolism; Protein Kinase C/physiology

Significance

Annotations

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

MOUSE:FLOT1

involved_in

GO:0002090: regulation of receptor internalization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q61327)
  • happens_during:(GO:0070528)

Seeded From UniProt

complete

MOUSE:FLOT1

involved_in

GO:0032226: positive regulation of synaptic transmission, dopaminergic

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q61327)
  • happens_during:(GO:0070528)

Seeded From UniProt

complete

MOUSE:FLOT1

involved_in

GO:0045807: positive regulation of endocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q61327)
  • happens_during:(GO:0070528)

Seeded From UniProt

complete

MOUSE:FLOT1

involved_in

GO:0070528: protein kinase C signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q61327)

Seeded From UniProt

complete

HUMAN:FLOT1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0005589: confocal microscopy evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0006052: RNAi evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0006063: over expression analysis evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLOT1

located_in

GO:0098691: dopaminergic synapse

ECO:0005589: confocal microscopy evidence used in manual assertion

C

  • part_of:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

located_in

GO:0098691: dopaminergic synapse

ECO:0006052: RNAi evidence used in manual assertion

C

  • part_of:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

located_in

GO:0098691: dopaminergic synapse

ECO:0006063: over expression analysis evidence used in manual assertion

C

  • part_of:(UBERON:0002691)

Seeded From UniProt

complete

RAT:SC6A3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000700)

Seeded From UniProt

complete

HUMAN:EAA2

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SC6A3

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SC6A3

part_of

GO:0016600: flotillin complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SC6A3

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SC6A3

part_of

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0098691: dopaminergic synapse

ECO:0006063: over expression analysis evidence used in manual assertion

C

part_of:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0098691: dopaminergic synapse

ECO:0006052: RNAi evidence used in manual assertion

C

part_of:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0098691: dopaminergic synapse

ECO:0005589: confocal microscopy evidence used in manual assertion

C

part_of:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0006063: over expression analysis evidence used in manual assertion

P

  • occurs_in:(GO:0098691)
  • occurs_in:(UBERON:0000061)
  • occurs_in:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0006052: RNAi evidence used in manual assertion

P

  • occurs_in:(GO:0098691)
  • occurs_in:(UBERON:0000061)
  • occurs_in:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051580: regulation of neurotransmitter uptake

ECO:0005589: confocal microscopy evidence used in manual assertion

P

  • occurs_in:(GO:0098691)
  • occurs_in:(UBERON:0000061)
  • occurs_in:(UBERON:0002691)

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0070528: protein kinase C signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0045807: positive regulation of endocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q01959)
  • happens_during:(GO:0070528)
  • has_input:(UniProtKB:P43004)

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0002090: regulation of receptor internalization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q01959)
  • happens_during:(GO:0070528)
  • has_input:(UniProtKB:P43004)

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0051260: protein homooligomerization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLOT1

part_of

GO:0016600: flotillin complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0044854: plasma membrane raft assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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