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PMID:12239163

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Citation

Park, SM, Jung, HY, Kim, HO, Rhim, H, Paik, SR, Chung, KC, Park, JH and Kim, J (2002) Evidence that alpha-synuclein functions as a negative regulator of Ca(++)-dependent alpha-granule release from human platelets. Blood 100:2506-14

Abstract

alpha-Synuclein has been implicated in the pathogenesis of Parkinson disease (PD) and related neurodegenerative disorders. More recently, it has been suggested to be an important regulatory component of vesicle transport in neuronal cells. alpha-Synuclein is also highly expressed in platelets and is loosely associated with the membrane of the secretory alpha-granules. However, the functional significance of these observations is unknown. In this study, the possible function of alpha-synuclein in vesicle transport, with particular regard to alpha-granule release from the platelets, was investigated. The results showed that ionomycin- or thrombin-induced alpha-granule secretion was inhibited by exogenous alpha-synuclein addition in a dose-dependent manner. However, [(3)H]5-HT release from the dense granules and hexosaminidase release from the lysosomal granules were not affected. Two point mutants (A30P and A53T) found in some familial types of PD, in addition to beta-synuclein and alpha-synuclein112, effectively inhibited PF4 release from the alpha-granules. However, the deletion mutants, which completely lacked either the N-terminal region or the C-terminal tail, did not affect alpha-granule release. Interestingly, exogenously added alpha-synuclein appeared to enter the platelets but did not change the Ca(++) level in the platelets at the resting state and the increase in the Ca(++) level on stimulation. Electron microscopy also supported that alpha-synuclein inhibits alpha-granule release. These results suggest that alpha-synuclein may function as a specific negative regulator of alpha-granule release in platelets.

Links

PubMed Online version:10.1182/blood.V100.7.2506

Keywords

Blood Platelets/drug effects; Blood Platelets/physiology; Blood Platelets/ultrastructure; Calcium/blood; Cytoplasmic Granules/drug effects; Cytoplasmic Granules/physiology; Cytoplasmic Granules/ultrastructure; Humans; Ionomycin/pharmacology; Kinetics; Microscopy, Electron; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/pharmacology; Nerve Tissue Proteins/physiology; Neurodegenerative Diseases/physiopathology; Point Mutation; Recombinant Proteins/pharmacology; Synucleins; Thrombin/pharmacology; alpha-Synuclein; beta-Synuclein

Significance

Annotations

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

HUMAN:SYUA

involved_in

GO:0045920: negative regulation of exocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

colocalizes_with

GO:0031092: platelet alpha granule membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0010642: negative regulation of platelet-derived growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

NOT|involved_in

GO:0055074: calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SYUA

involved_in

GO:0070495: negative regulation of thrombin-activated receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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