ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Phosphatidylinositol-4,5-bisphosphate regulates NMDA receptor activity through alpha-actinin.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 57 citations in OpenAlex.
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- Resting-state brain functional alterations and their genetic mechanisms in drug-naive first-episode psychosis.Schizophrenia (Heidelberg, Germany) · 2023Article
- Roles of Cholesterol and PtdIns(4,5)PAdvances in experimental medicine and biology · 2023Review
- Cross-Talk between P2X and NMDA Receptors.International journal of molecular sciences · 2020Article
- Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels.Biochimica et biophysica acta. Biomembranes · 2020Review
- Cytoskeleton disruption affects Kv2.1 channel function and its modulation by PIPThe journal of physiological sciences : JPS · 2019Article
- Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert.Neuron · 2018Review
- Mice Deficient inMolecular and cellular biology · 2017Article
- Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex.Nature communications · 2015Article
- Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis.Journal of neuroinflammation · 2015Article
- Lipid agonism: The PIP2 paradigm of ligand-gated ion channels.Biochimica et biophysica acta · 2015Review
- Phosphoinositide control of membrane protein function: a frontier led by studies on ion channels.Annual review of physiology · 2015Review
- The role of phosphoinositides in synapse function.Molecular neurobiology · 2014Review
- Phosphatidylinositol 4,5-bisphosphate depletion fails to affect neurosteroid modulation of GABAA receptor function.Psychopharmacology · 2014Article
- α-Actinin-2 mediates spine morphology and assembly of the post-synaptic density in hippocampal neurons.PloS one · 2014Article
- Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB activity in lumbosacral spinal cord in cystitis.Experimental neurology · 2013Article
- Post-translational regulation of P2X receptor channels: modulation by phospholipids.Frontiers in cellular neuroscience · 2013Review
- Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2013Article
- Phosphoinositides: tiny lipids with giant impact on cell regulation.Physiological reviews · 2013Review
- Two structural components in CNGA3 support regulation of cone CNG channels by phosphoinositides.The Journal of general physiology · 2013Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphatidylinositol-4,5-bisphosphate (PIP2) has been shown to regulate many ion channels, transporters, and other signaling proteins, but it is not known whether it also regulates neurotransmitter-gated channels. The NMDA receptors (NMDARs) are gated by glutamate and serve as a critical control point in synaptic function. Here we demonstrate that PIP2 supports NMDAR activity. In Xenopus oocytes, overexpression of phospholipase Cgamma (PLCgamma) or preincubation with 10 microm wortmannin markedly reduced NMDA currents. Stimulation of the epidermal growth factor receptor (EGFR) promoted the formation of an immunocomplex between PLCgamma and NMDAR subunits. Stimulation of EGFR or the PLCbeta-coupled M1 acetylcholine receptor produced a robust transient inhibition of NMDA currents. Wortmannin application blocked the recovery of NMDA currents from the inhibition. Using mutagenesis, we identified the structural elements on NMDAR intracellular tails that transduce the receptor-mediated inhibition, which pinpoint to the binding site for the cytoskeletal protein alpha-actinin. Mutation of the PIP2-binding residues of alpha-actinin dramatically reduced NMDA currents and occluded the effect of EGF. Interestingly, EGF or wortmannin affected the interaction between NMDAR subunits and alpha-actinin, suggesting that this protein mediates the effect of PIP2 on NMDARs. In mature hippocampal neurons, expression of the mutant alpha-actinin reduced NMDA currents and accelerated inactivation. We propose a model in which alpha-actinin supports NMDAR activity via tethering their intracellular tails to plasma membrane PIP2. Thus, our results extend the influence of PIP2 to the NMDA ionotropic glutamate receptors and introduce a novel mechanism of "indirect" regulation of transmembrane protein activity by PIP2.
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