15451
Modulation of the Serotonin Transporter By Interaction with N-Ethylmaleimide-Sensitive Factor
Saturday, May 17, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
K. Iwata1, H. Matsuzaki
2, T. Katayama
3 and N. Mori
4, (1)Fukui Univ., Fukui, Fukui, Japan, (2)Research Center for Child Mental Development, University of Fukui, Fukui, Japan, (3)Osaka University United Graduate School of Child Development, Suita, Japan, (4)Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
Background: Many studies on the pathophysiologic mechanism
of autism have focused on the serotonergic system. Prior studies
consistently found elevated serotonin levels in the whole blood
cells and platelets of patients with autism. Importantly, our colleagues reported that serotonin transporter (SERT) and its radioligand binding was significantly lower throughout the brain in autistic individuals compared with controls (Nakamura et al., 2010). These clinical evidences suggest that SERT function may be disturbed in autism. The functions of neurotransmitter transporters are influenced both by the number of transporter molecules present at the cell surface and by the intrinsic activity of individual transporter molecules. It is known that the number and activity are regulated by proteins which interact with transporter. Several SERT-interacting proteins, such as SCAMP2, nNOS, Hic-5 and syntaxin-1A, have been identified mainly by yeast two-hybrid screens. However, it is little known whether some of these proteins bind SERT in the mammalian brain.
Objectives: In this study, we sought to identify novel SERT-interacting proteins and investigate whether one of such protein regulates SERT function.
Methods: Novel SERT-binding proteins were examined by a pull-down system. Alterations of SERT function and membrane expression upon knockdown of the novel SERT-binding protein were studied in HEK293-hSERT cells. Endogenous interaction of SERT with the protein was evaluated in mouse brains.
Results: N-ethylmaleimide-sensitive factor (NSF) was identified as a novel SERT-binding protein. NSF co-localized with SERT at the plasma membrane, and NSF knockdown resulted in decreased SERT expression at the cell membranes and its uptake function. NSF endogenously co-localized with SERT and interacted with SERT.
Conclusions: It has been reported that NSF interacts with some neurotransmitter receptors, such as glutamate, adrenaline, and dopamine receptors, and regulate membrane trafficking of these receptors. Since it has been reported that many of these receptors are abnormal in autism, it is possible that NSF plays a key role in the pathophysiology of the disorder.
