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Publication
Colocalization and regulated physical association of presynaptic serotonin
transporters with A3 adenosine receptors.
Authors Zhu CB, Lindler KM, Campbell NG, Sutcliffe JS, Hewlett WA, Blakely RD
Submitted By Randy Blakely on 9/18/2012
Status Published
Journal Molecular pharmacology
Year 2011
Date Published 9/1/2011
Volume : Pages 80 : 458 - 465
PubMed Reference 21705486
Abstract Activation of A3 adenosine receptors (A3ARs) rapidly enhances the activity of
antidepressant-sensitive serotonin (5-HT) transporters (SERTs) in vitro, ex
vivo, and in vivo. A3AR agonist stimulation of SERT activity is lost in A3AR
knockout mice. A3AR-stimulated SERT activity is mediated by protein kinase G1
(PKGI)- and p38 mitogen-activated protein kinase (MAPK)-linked pathways that
support, respectively, enhanced SERT surface expression and catalytic
activation. The mechanisms by which A3ARs target SERTs among other potential
effectors is unknown. Here we present evidence that A3ARs are coexpressed with
SERT in midbrain serotonergic neurons and form a physical complex in A3AR/hSERT
cotransfected cells. Treatment of A3AR/SERT-cotransfected Chinese hamster ovary
cells with the A3AR agonist N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (1
µM, 10 min), conditions previously reported to increase SERT surface expression
and 5-HT uptake activity, enhanced the abundance of A3AR/SERT complexes in a
PKGI-dependent manner. Cotransfection of SERT with L90V-A3AR, a hyperfunctional
coding variant identified in subjects with autism spectrum disorder, resulted in
a prolonged recovery of receptor/transporter complexes after A3AR activation.
Because PKGI and nitric-oxide synthetase are required for A3AR stimulation of
SERT activity, and proteins PKGI and NOS both form complexes with SERT, our
findings suggest a mechanism by which signaling pathways coordinating A3AR
signaling to SERT can be spatially restricted and regulated, as well as
compromised by neuropsychiatric disorders.




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