Publications (2)8.83 Total impact
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Article: Control of excitatory synaptic transmission by C-terminal Src kinase.
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ABSTRACT: The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus.Journal of Biological Chemistry 07/2008; 283(25):17503-14. · 4.77 Impact Factor -
Article: Protein kinase C enhances glycine-insensitive desensitization of NMDA receptors independently of previously identified protein kinase C sites.
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ABSTRACT: Protein kinase C (PKC) phosphorylates the NR1 and NR2A subunits of NMDARs at consensus sites located within their intracellular C-terminal tails. However, the functional consequences of these biochemical events are not well understood. In HEK293 cells expressing NR1/NR2A, activation of endogenous PKC by 4beta-phorbol 12-myristate 13-acetate (PMA) increased NMDAR desensitization as evidenced by a reduced steady-state current without any change in peak. The effects of PMA on NMDAR-mediated responses were prevented by specific PKC inhibitors and were not mimicked by an inactive enantiomer of PMA. The effects of PMA were preserved despite mutagenesis of the major PKC sites on the NR1 subunit (S889A, S890A, S896A and S897A) or removal of the entire NR1 C-terminal tail (NR1(stop838)). When co-expressing NR1(stop838)/NR2A the effects of PMA could only be observed with agonist concentrations sufficient to induce glycine-insensitive desensitization. Moreover, the effects of PMA were observed in receptors composed of NR1/NR2A and NR1/NR2B, but not NR1/NR2C, a subunit combination in which desensitization is absent. The NR2 subunit dependence suggested that the actions of PMA might require specific PKC sites previously identified within NR2A. However, a C-terminal truncated form of NR2A (NR2A(stop905)) remained responsive to PMA. We conclude that activation of PKC increases NMDAR glycine-insensitive desensitization independently of previously identified sites located within the NR1 C-terminus and distal segment of the NR2A C-terminus.Journal of Neurochemistry 04/2006; 96(6):1509-18. · 4.06 Impact Factor
