Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABABreceptors

Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs). GABA B Rs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABA B Rs are predominantly found on den...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (31), p.13918-13923
Main Authors: Terunuma, Miho, Vargas, Karina J., Wilkins, Megan E., Ramírez, Omar A., Jaureguiberry-Bravo, Matías, Pangalos, Menelas N., Smart, Trevor G., Moss, Stephen J., Couve, Andrés, Huganir, Richard L.
Format: Article
Language:English
Subjects:
Antibodies
Cell membranes
Endocytosis
Immunoblotting
Neurons
Neuroscience
Phosphorylation
Physiological regulation
Receptors
Recycling
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Summary:Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs). GABA B Rs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABA B Rs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of GABA B Rs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of GABA B Rs. These sorting events are paralleled by a reduction in GABA B R-dependent activation of inwardly rectifying K⁺ channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the GABA B R2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of GABA B Rs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of GABA B Rs at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors.
ISSN:0027-8424
1091-6490