PMID- 20176067
OWN - NLM
STAT- MEDLINE
DCOM- 20100729
LR  - 20211020
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Print)
IS  - 0197-0186 (Linking)
VI  - 56
IP  - 6-7
DP  - 2010 May-Jun
TI  - Reserpine-induced reduction in norepinephrine transporter function requires 
      catecholamine storage vesicles.
PG  - 760-7
LID - 10.1016/j.neuint.2010.02.011 [doi]
AB  - Treatment of rats with reserpine, an inhibitor of the vesicular monoamine 
      transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter 
      (NET) expression. The present study examined the molecular mechanisms involved in 
      regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 
      cells to reserpine for a period as short as 5min decreased [(3)H]NE uptake 
      capacity, an effect characterized by a robust decrease in the V(max) of the 
      transport of [(3)H]NE. As expected, reserpine did not displace the binding of 
      [(3)H]nisoxetine from the NET in membrane homogenates. The potency of reserpine 
      for reducing [(3)H]NE uptake was dramatically lower in SK-N-SH cells that have 
      reduced storage capacity for catecholamines. Reserpine had no effect on [(3)H]NE 
      uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack 
      catecholamine storage vesicles. NET regulation by reserpine was independent of 
      trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors 
      of several intracellular signaling cascades known to regulate the NET, including 
      Ca(2+)/Ca(2+)-calmodulin dependent kinase and protein kinases A, C and G, did not 
      affect the ability of reserpine to reduce [(3)H]NE uptake. Treatment of PC12 
      cells with the catecholamine depleting agent, alpha-methyl-p-tyrosine, increased 
      [(3)H]NE uptake and eliminated the inhibitory effects of reserpine on [(3)H]NE 
      uptake. Reserpine non-competitively inhibits NET activity through a 
      Ca(2+)-independent process that requires catecholamine storage vesicles, 
      revealing a novel pharmacological method to modify NET function. Further 
      characterization of the molecular nature of reserpine's action could lead to the 
      development of alternative therapeutic strategies for treating disorders known to 
      be benefitted by treatment with traditional competitive NET inhibitors.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Mandela, Prashant
AU  - Mandela P
AD  - Department of Pharmacology & Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216, USA.
FAU - Chandley, Michelle
AU  - Chandley M
FAU - Xu, Yao-Yu
AU  - Xu YY
FAU - Zhu, Meng-Yang
AU  - Zhu MY
FAU - Ordway, Gregory A
AU  - Ordway GA
LA  - eng
GR  - R01 MH080323/MH/NIMH NIH HHS/United States
GR  - R01 MH046692-15/MH/NIMH NIH HHS/United States
GR  - K02 MH002031-06/MH/NIMH NIH HHS/United States
GR  - R01 MH058211-04/MH/NIMH NIH HHS/United States
GR  - R01 MH046692/MH/NIMH NIH HHS/United States
GR  - K02 MH002031/MH/NIMH NIH HHS/United States
GR  - MH02031/MH/NIMH NIH HHS/United States
GR  - R01 MH080323-02/MH/NIMH NIH HHS/United States
GR  - MH58211/MH/NIMH NIH HHS/United States
GR  - MH46692/MH/NIMH NIH HHS/United States
GR  - MH080323/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100220
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Adrenergic Uptake Inhibitors)
RN  - 0 (Catecholamines)
RN  - 0 (Norepinephrine Plasma Membrane Transport Proteins)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 10028-17-8 (Tritium)
RN  - 17NV064B2D (nisoxetine)
RN  - 8B1QWR724A (Reserpine)
RN  - EC 2.7.- (Protein Kinases)
RN  - SY7Q814VUP (Calcium)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Adrenergic Uptake Inhibitors/*pharmacology
MH  - Animals
MH  - Calcium/pharmacology
MH  - Catecholamines/*metabolism
MH  - Cytoplasmic Vesicles/*metabolism
MH  - Fluoxetine/analogs & derivatives/metabolism
MH  - Kinetics
MH  - Norepinephrine/antagonists & inhibitors/metabolism
MH  - Norepinephrine Plasma Membrane Transport Proteins/*antagonists & 
      inhibitors/genetics/*physiology
MH  - PC12 Cells
MH  - Protein Kinases/metabolism
MH  - Rats
MH  - Reserpine/*pharmacology
MH  - Transfection
MH  - Tritium
PMC - PMC2859979
MID - NIHMS182531
EDAT- 2010/02/24 06:00
MHDA- 2010/07/30 06:00
PMCR- 2011/05/01
CRDT- 2010/02/24 06:00
PHST- 2009/11/16 00:00 [received]
PHST- 2010/02/09 00:00 [revised]
PHST- 2010/02/12 00:00 [accepted]
PHST- 2010/02/24 06:00 [entrez]
PHST- 2010/02/24 06:00 [pubmed]
PHST- 2010/07/30 06:00 [medline]
PHST- 2011/05/01 00:00 [pmc-release]
AID - S0197-0186(10)00071-9 [pii]
AID - 10.1016/j.neuint.2010.02.011 [doi]
PST - ppublish
SO  - Neurochem Int. 2010 May-Jun;56(6-7):760-7. doi: 10.1016/j.neuint.2010.02.011. 
      Epub 2010 Feb 20.