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Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase

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Abstract

GLUTAMATE-GATED ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions1–3. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors4. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A–D), AMPA (GluRl–4) and KA (GluR5–7, KA1, KA2) receptors5–7. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function8–18, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation19 and long-term depression9. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.

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Authors and Affiliations

  1. Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Craig D. Blackstone & Richard L. Huganir

  2. Department of Neurology, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Lynn A. Raymond

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  1. Lynn A. Raymond
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  2. Craig D. Blackstone
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  3. Richard L. Huganir
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Raymond, L., Blackstone, C. & Huganir, R. Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. Nature 361, 637–641 (1993). https://doi.org/10.1038/361637a0

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