Abstract/Details

Norepinephrine transporter regulation by reserpine and potassium chloride stimulation: Role of intracellular signaling cascades


2006 2006

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Abstract (summary)

The norepinephrine transporter (NET) is present on the plasma membrane of noradrenergic neurons and is responsible for norepinephrine (NE) reuptake. The NET is under intrinsic regulation by cellular processes that affect concentrations of intracellular NE, by receptors, and by kinase-linked pathways. Clarification of these pathways may implicate candidate proteins for pharmacological targeting that could ultimately lead to the development of novel therapeutic agents. The overall goal of this research was to elucidate the potential role of intracellular NE stores in regulating NET function and the second messenger systems that are recruited in this process. Three different procedures for reducing intracellular NE were studied, NE synthesis inhibition, vesicular monoamine transporter (VMAT) inhibition, and repeated KC1 stimulation. NET function was assessed in two cell lines, rat PC12 and human SK-N-SH cells. Treatment of cells with a tyrosine hydroxylase inhibitor to inhibit NE synthesis did not affect NET function. In contrast, treatment with a VMAT inhibitor (reserpine) decreased NE uptake in both cell lines. KCl stimulation increased NE uptake in PC12 cells, but had no effect on SK-N-SH cells. Experiments demonstrated that reserpine did not alter the plasma membrane surface expression of the NET, but failed to identify an intracellular mediator of the effect of reserpine on NET function, leaving the possibility that reserpine directly binds the NET at a novel and as yet unknown site on the protein. The KCl stimulated increase in NE uptake was dependent on Ca2+ and was blocked by inhibitors of Ca 2+-calmodulin dependent kinase and myosin light chain kinase. The increase in NE uptake following KCl stimulation was not accompanied by a change in the surface expression of the transporter. Given that the three NE depleting procedures had different effects on NET function, the findings do not support the hypothesis that NET function is regulated to support intracellular stores of NE. Different degrees of NE depletion produced by each method and/or direct binding to the NET and interference with its function could have contributed to the different effects on NET function.

Indexing (details)


Subject
Neurology;
Pharmacology
Classification
0317: Neurology
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; Biological sciences; Norepinephrine; Potassium chloride; Reserpine; Signaling cascades
Title
Norepinephrine transporter regulation by reserpine and potassium chloride stimulation: Role of intracellular signaling cascades
Author
Mandela, Prashant
Number of pages
183
Publication year
2006
Degree date
2006
School code
0805
Source
DAI-B 68/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Advisor
Farley, Jerry M.
University/institution
The University of Mississippi Medical Center
University location
United States -- Mississippi
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3247775
ProQuest document ID
304932644
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304932644
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