PMID- 18317590
OWN - NLM
STAT- MEDLINE
DCOM- 20080516
LR  - 20211020
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 118
IP  - 4
DP  - 2008 Apr
TI  - Interactions between integrin alphaIIbbeta3 and the serotonin transporter 
      regulate serotonin transport and platelet aggregation in mice and humans.
PG  - 1544-52
LID - 10.1172/JCI33374 [doi]
AB  - The essential contribution of the antidepressant-sensitive serotonin (5-HT) 
      transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores 
      suggests an important role of this transporter in platelet function. Here, using 
      SERT-deficient mice, we have established a role for constitutive SERT expression 
      in efficient ADP- and thrombin-triggered platelet aggregation. Additionally, 
      using pharmacological blockers of SERT and the vesicular monoamine transporter 
      (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in 
      efficient human platelet aggregation. We have also demonstrated that fibrinogen, 
      an activator of integrin alphaIIbbeta3, enhances SERT activity in human platelets 
      and that integrin alphaIIbbeta3 interacts directly with the C terminus of SERT. 
      Consistent with these findings, knockout mice lacking integrin beta3 displayed 
      diminished platelet SERT activity. Conversely, HEK293 cells engineered to express 
      human SERT and an activated form of integrin beta3 exhibited enhanced SERT 
      function that coincided with elevated SERT surface expression. Our results 
      support an unsuspected role of alphaIIbbeta3/SERT associations as well as 
      alphaIIbbeta3 activation in control of SERT activity in vivo that may have broad 
      implications for hyperserotonemia, cardiovascular disorders, and autism.
FAU - Carneiro, Ana Marin D
AU  - Carneiro AM
AD  - Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, 
      Tennessee 37232-8548, USA.
FAU - Cook, Edwin H
AU  - Cook EH
FAU - Murphy, Dennis L
AU  - Murphy DL
FAU - Blakely, Randy D
AU  - Blakely RD
LA  - eng
GR  - P50 MH078028/MH/NIMH NIH HHS/United States
GR  - U19 HD035482/HD/NICHD NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - U19 HD35482/HD/NICHD NIH HHS/United States
GR  - DA007390/DA/NIDA NIH HHS/United States
GR  - R01 DA007390/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Platelet Glycoprotein GPIIb-IIIa Complex)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 333DO1RDJY (Serotonin)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Biological Transport
MH  - Blood Platelets/*cytology/*metabolism
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - Mice
MH  - Mice, Knockout
MH  - *Platelet Aggregation
MH  - Platelet Glycoprotein GPIIb-IIIa Complex/genetics/*metabolism
MH  - Protein Binding
MH  - Protein Phosphatase 1/metabolism
MH  - Protein Phosphatase 2/metabolism
MH  - Serotonin/*metabolism
MH  - Serotonin Plasma Membrane Transport Proteins/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC2260909
EDAT- 2008/03/05 09:00
MHDA- 2008/05/17 09:00
PMCR- 2008/04/01
CRDT- 2008/03/05 09:00
PHST- 2007/07/23 00:00 [received]
PHST- 2008/01/09 00:00 [accepted]
PHST- 2008/03/05 09:00 [pubmed]
PHST- 2008/05/17 09:00 [medline]
PHST- 2008/03/05 09:00 [entrez]
PHST- 2008/04/01 00:00 [pmc-release]
AID - 33374 [pii]
AID - 10.1172/JCI33374 [doi]
PST - ppublish
SO  - J Clin Invest. 2008 Apr;118(4):1544-52. doi: 10.1172/JCI33374.