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The Journal of Neuroscience, December 7, 2005, 25(49):11374-11384; doi:10.1523/JNEUROSCI.3871-05.2005

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Cellular/Molecular
Modulation of NMDA Receptors by Pituitary Adenylate Cyclase Activating Peptide in CA1 Neurons Requires G_q, Protein Kinase C, and Activation of Src

D. S. Macdonald,^2 * M. Weerapura,^1 * M. A. Beazely,¹ L. Martin,⁴ W. Czerwinski,¹ J. C. Roder,³ B. A. Orser,^1,4 and J. F. MacDonald^1,2

Departments of ¹Physiology, ²Pharmacology, and ³Immunology and ⁴Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada M5S 1A8

At CA1 synapses, activation of NMDA receptors (NMDARs) is required for the induction of both long-term potentiation and depression. The basal level of activity of these receptors is controlled by converging cell signals from G-protein-coupled receptors and receptor tyrosine kinases. Pituitary adenylate cyclase activating peptide (PACAP) is implicated in the regulation of synaptic plasticity because it enhances NMDAR responses by stimulating G_s-coupled receptors and protein kinase A (Yaka et al., 2003). However, the major hippocampal PACAP1 receptor (PAC₁R) also signals via G_q subunits and protein kinase C (PKC). In CA1 neurons, we showed that PACAP38 (1 nM) enhanced synaptic NMDA, and evoked NMDAR, currents in isolated CA1 neurons via activation of the PAC₁R, G_q, and PKC. The signaling was blocked by intracellular applications of the Src inhibitory peptide Src(40-58). Immunoblots confirmed that PACAP38 biochemically activates Src. A G_q pathway is responsible for this Src-dependent PACAP enhancement because it was attenuated in mice lacking expression of phospholipase C 1, it was blocked by preventing elevations in intracellular Ca²⁺, and it was eliminated by inhibiting either PKC or cell adhesion kinase [CAK or Pyk2 (proline rich tyrosine kinase 2)]. Peptides that mimic the binding sites for either Fyn or Src on receptor for activated C kinase-1 (RACK1) also enhanced NMDAR in CA1 neurons, but their effects were blocked by Src(40-58), implying that Src is the ultimate regulator of NMDARs. RACK1 serves as a hub for PKC, Fyn, and Src and facilitates the regulation of basal NMDAR activity in CA1 hippocampal neurons.

Key words: hippocampus; NMDA; Src; kinase; PACAP; pituitary adenylate cyclase activating peptide; signaling

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Received Sep 13, 2005; revised October 25, 2005; accepted October 28, 2005.

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