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The Journal of Neuroscience, July 2, 2003, 23(13):5827-5834

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NMDA and ₁-Adrenergic Receptors Differentially Signal Phosphorylation of Glutamate Receptor Type 1 in Area CA1 of Hippocampus

Amanda M. Vanhoose¹ and Danny G. Winder^1,2

¹Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, and ²John F. Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

Glutamatergic synaptic transmission is mediated primarily through the AMPA-type glutamate receptor (AMPAR); the regulation of this receptor underlies many forms of synaptic plasticity. In particular, phosphorylation of GluR1, an AMPAR subunit, by PKA at serine 845 (S845) increases peak open channel probability and is permissive for both the synaptic expression of the receptor and NMDA-receptor (NMDAR)-dependent long-term potentiation (LTP). Robust NMDAR activation activates PKA as well as other signaling enzymes; however, we find that maximal NMDAR activation dephosphorylates GluR1 at the PKA site S845. Coincident inhibition of phosphatases blocks NMDAR-induced dephosphorylation of S845, but surprisingly does not promote PKA phosphorylation at this site. However, we find that phosphorylation of S845 is increased by the activation of a G_s-coupled receptor, the ₁-adrenergic receptor. Interestingly, this divergent signaling occurs despite a more robust coupling of the NMDAR to cAMP generation. In addition, NMDAR activation plays a dominant role in S845 regulation, because activation of ₁AR after NMDAR activation has no detectable effect on S845 phosphorylation. These data (1) demonstrate highly specific coupling between these receptors and this substrate, (2) provide an example of a substrate critical in NMDAR-dependent LTP that is incompletely regulated by the NMDAR, and (3) highlight the importance of identifying the physiological signals that regulate these critical synaptic substrates.

Key words: synaptic plasticity; long-term potentiation; LTP; neuromodulation; neuromodulatory; AMPA receptor; PKA

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Received Mar. 13, 2003; revised May. 1, 2003; accepted May. 8, 2003.

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