Tyrosine Phosphorylation and Regulation of the AMPA Receptor by Src Family Tyrosine Kinases

Abstract

Phosphorylation of AMPA receptors is a major mechanism for the regulation of receptor function and underlies several forms of synaptic plasticity in the CNS. Although serine and threonine phosphorylation of AMPA receptors has been well studied, the potential role of tyrosine phosphorylation of AMPA receptors has not been investigated. Here, we show that the GluR2 subunit of AMPA receptors is tyrosine phosphorylated in vitro and in vivo by Src family tyrosine kinases on tyrosine 876 near its C terminus. In addition, GluR agonist treatment of cultured cortical neurons increased phosphorylation of tyrosine 876. The association with GluR2-interacting molecules GRIP1/2 was decreased by tyrosine phosphorylation of GluR2, whereas PICK1 interaction was not influenced. Moreover, mutation of tyrosine 876 eliminated AMPA-and NMDA-induced internalization of the GluR2 subunit. These data indicate that tyrosine phosphorylation of tyrosine 876 on the GluR2 C terminus by Src family tyrosine kinases is important for the regulation of AMPA receptor function and may be important for synaptic plasticity.

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

“…SFKs can be modulated by tyrosine phosphatases, G-protein-coupled receptors, receptor protein tyrosine kinase signaling, the Ras pathway, and the cytokine receptor and integrin pathways. Many of the physiological actions of NMDA receptors are critically dependent upon SFKs (Gingrich et al, 2004;Hayashi and Huganir, 2004;Kalia and Salter, 2003;Lu et al, 1999). As an example, SFKs are necessary for the induction of long-term potentiation in the CA1 region of hippocampus (Salter and Kalia, 2004).…”

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

“…Alternatively, increased NMDAR currents may be partly attributable to increased NMDAR trafficking to postsynaptic sites, as happens during certain forms of synaptic activity (Lan et al, 2001;Grosshans et al, 2002;Chung et al, 2004). Similarly, increased AMPAR responses after reelin application may result from enhanced single-channel activity through phosphorylation of specific Ser/Thr or tyrosine residues (Barria et al, 1997;Banke et al, 2000;Lee et al, 2000;Hayashi and Huganir, 2004) or from increased AMPAR trafficking to the synaptic sites (Shi et al, 1999;Hayashi et al, 2000;Man et al, 2003). We therefore first examined the phosphorylation levels of two serine residues of AMPAR subunit GluR1, Ser831 and Ser845; both can be increased during certain forms of synaptic plasticity (Barria et al, 1997;Lee et al, 2000).…”

“…5A) (n ϭ 4; data not shown). Given that reelin application leads to Src activation and that tyrosine phosphorylation of AMPAR subunits by Src has been recently established as another major mechanism for regulated AMPAR endocytosis and receptor function during plasticity (Ahmadian et al, 2004;Hayashi and Huganir, 2004), we next examined levels of tyrosine phosphorylation of GluR1 and GluR2/3 subunits by immunoprecipitating CA1 tissue with GluR1 and GluR2/3 antibodies followed by immunoblotting with pY, GluR1, and GluR2/3 antibodies. No significant changes of tyrosine phosphorylation of either GluR1 or GluR2/3 subunits were observed.…”

Regulation of AMPA receptors and synaptic plasticity

“…1B) (Hayashi and Huganir, 2004). Interestingly, phosphorylation of this tyrosine residue has similar effects to the phosphorylation of Ser880.…”

“…Interestingly, phosphorylation of this tyrosine residue has similar effects to the phosphorylation of Ser880. Phosphorylation of GluR2 on Tyr876 decreases the binding to GRIP1/ABP, but is without effect on the binding to PICK1, thus facilitating the AMPA-or NMDA-induced receptor internalization (Hayashi and Huganir, 2004).…”