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.

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.