STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit.

Meng Tian,Gang Lei,Jian Xu,Michael F Jackson,John F Macdonald,Paul J Lombroso

doi:10.1038/srep36684

Abstract

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A. STEP activation by M1R stimulation requires IP3Rs and can depress NMDA-evoked currents with modest intracellular Ca2+ buffering. Src recruitment by M1R stimulation requires coincident NMDAR activation and can augment NMDA-evoked currents with high intracellular Ca2+ buffering. Our findings suggest that Src and STEP recruitment is contingent on differing intracellular Ca2+ dynamics that dictate whether NMDAR function is augmented or depressed following M1R stimulation.

Highlights

Postsynaptic NMDA receptors in CA1 hippocampal neurons are required for the induction of synaptic plasticity and contribute to the consolidation of hippocampal based learning and memory
When hippocampal CA3 neurons were treated with a non-specific tyrosine phosphatase inhibitor, the inhibition of N-methyl-D-aspartate receptors (NMDARs) currents by muscarine was converted to a potentiation[12]
We investigated whether protein tyrosine phosphatase (PTP) limit the ability of Src kinase to enhance NMDAR currents downstream of Gαq-coupled G-protein coupled receptors (GPCRs) stimulation in CA1 hippocampal neurons

Summary

Introduction

Postsynaptic NMDA receptors in CA1 hippocampal neurons are required for the induction of synaptic plasticity and contribute to the consolidation of hippocampal based learning and memory. Neuronal signalling downstream of GluN2ARs and GluN2BRs mediate distinct functional outcomes, within the hippocampus but within other CNS regions as well This includes opposing contributions to the induction of synaptic plasticity, neuronal survival and cell death[1,2,5]. Activation of Gαq-coupled muscarinic acetylcholine receptors (mAchRs) potentiates NMDARs8–10 and enhances NMDAR-dependent LTP11. They can depress NMDARs9,12 and promote the induction of NMDAR-dependent LTD13,14. These results present a conundrum in that mAChRs both enhance or depress NMDAR currents in hippocampal neurons We have resolved this conundrum by testing the hypothesis that GαqGPCRs, including M1 mAChRs (M1Rs), recruit both Src kinase and the striatal-enriched protein tyrosine phosphatase (STEP) concurrently. The mechanisms described are likely to be important determinants of metaplasticity

Methods

Results

Conclusion