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The Journal of Neuroscience, January 25, 2006, 26(4):1138-1145; doi:10.1523/JNEUROSCI.3572-05.2006

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Cellular/Molecular
Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors

Amanda M. Vanhoose,¹ Julie M. Clements,¹ and Danny G. Winder^1,2

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

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 724B, Robinson Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

The phosphorylation state of the glutamate receptor subtype 1 (GluR1) subunit of the AMPA receptor (AMPAR) plays a critical role in synaptic expression of the receptor, channel properties, and synaptic plasticity. Several G_s-coupled receptors that couple to protein kinase A (PKA) readily recruit phosphorylation of GluR1 at S845. Conversely, activation of the ionotropic glutamate NMDA receptor (NMDAR) readily recruits dephosphorylation of the same GluR1 site through Ca²⁺-mediated recruitment of phosphatase activity. In a physiological setting, receptor activation often overlaps and crosstalk between coactivation of multiple signaling cascades can result in differential regulation of a given substrate. After investigating the effect of coactivation of the NMDAR and the G_s-coupled -adrenergic receptor on GluR1 phosphorylation state, we have observed a novel signal that prevents PKA-mediated phosphorylation of GluR1 at serine site 845. This blockade of GluR1 phosphorylation is dependent on cellular depolarization recruited by either NMDAR or AMPAR activation, independent of Ca²⁺ and independent of calcineurin, protein phosphatase 1, and/or protein phosphatase 2A activity. Thus, in addition to the typical kinase–phosphatase rivalry mediating protein phosphorylation state, we have identified a novel form of phospho-protein regulation that occurs at GluR1 and may also occur at several other PKA substrates.

Key words: AMPA receptor; -adrenergic receptor; NMDA receptor; CA1; depolarization; cAMP-dependent protein kinase

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Received June 7, 2005; revised Oct. 26, 2005; accepted Dec. 12, 2005.

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 724B, Robinson Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

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