Sci. STKE, 24 January 2006
SCHIZOPHRENIA This Is Spinal Trap
Various lines of evidence suggest that schizophrenia is associated with decreased signaling through N-methyl-D-aspartate type glutamate receptors (NMDARs) and a shift in the balance of dopamine signaling toward dopamine D2 compared with D1 receptors (D1Rs); thus, it is intriguing that interactions between NMDARs and D1Rs have been described. Scott et al. showed that, within minutes of exposure, NMDA elicited an increase in fluorescently labeled D1Rs in the dendritic spines of neurons in organotypic cultures from rat striatum without affecting the ratio between D1R in the dendritic cytoplasm and plasma membrane. Fluorescence recovery after photobleaching (FRAP) analysis revealed that, in the dendrites of untreated neurons, most D1Rs were mobile and likely localized to plasma membrane. The D1R diffusion coefficient was lower in spines than in nearby dendrite segments, and NMDA reduced the diffusion coefficient, which suggests that NMDA promoted the entrapment in dendritic spines of D1R diffusing laterally in the plasma membrane. Mutational analysis suggested that NMDA-dependent entrapment of D1R involved a direct interaction between D1Rs and NMDARs. Experiments in which calcium influx through the NMDAR in response to NMDA was blocked by magnesium or was stimulated with glycine indicated that NMDA-dependent trapping of the D1R in dendritic spines occurred independently of calcium influx. Thus, the authors propose that D1R recruitment to spines depends on an allosteric change in the NMDAR and that this system may represent a viable target for antipsychotic therapy.
L. Scott, S. Zelenin, S. Malmersjö, J. M. Kowalewski, E. Z. Markus, A. C. Nairn, P. Greengard, H. Brismar, A. Aperia, Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines. Proc. Natl. Acad. Sci. U.S.A. 103, 762-767 (2006). [Abstract] [Full Text]
Citation: This Is Spinal Trap. Sci. STKE 2006, tw34 (2006).
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