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DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in StrokeTu, Weihong, Xu, Xin, Peng, Lisheng, Zhong, Xiaofen, Zhang, Wenfeng, Soundarapandian, Mangala M., Balel, Cherine, Wang, Manqi, Jia, Nali, Zhang, Wen, Lew, Frank, Chan, Sic Lung, Chen, Yanfang, Lu, Youming 22 January 2010 (has links)
N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
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Connecting the Circadian Clock with ChemosensationChatterjee, Abhishek 2011 May 1900 (has links)
Chemoreception is a primitive sense universally employed by organisms for finding and
selecting food, rejecting toxic chemicals, detecting mates and offspring, choosing sites
for egg-laying, recognizing territories and avoiding predators. Chemosensory responses
are frequently modulated based on the internal environment of the organism. An
organism’s internal environment undergoes regular changes in anticipation and in
response to daily changes in its external environment, e.g., light-dark cycle. A resettable
timekeeping mechanism called the circadian clock internally drives these cyclical
changes with a ~24 hour period. Using electrophysiological, behavioral and molecular
analyses, I tested where and how these two conserved processes, viz., the circadian
timekeeping mechanism and the chemosensory pathway, intersect each other at
organismal and cellular levels.
The presence of autonomous peripheral oscillators in the chemosensory organs of
Drosophila, prompted us to test whether chemosensory responses are under control of
the circadian clock. I found that local oscillators in afferent (primary) chemosensory
neurons drive rhythms in physiological and behavioral responses to attractive and
aversive chemical signals. During the middle of the night, high level of G proteincoupled
receptor kinase 2 (GPRK2), a clock controlled signaling molecule present in
chemosensory neurons, suppresses tastant-evoked responses and promotes olfactory
responses. G-protein mediated signaling was shown to be involved in generating optimal
response to odorants. Multifunctional chemosensory clocks exert control on feeding and
metabolism. I propose that temporal plasticity in innate behaviors should offer adaptive
advantages to flies.
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