Pharmacological Studies of Synaptic Transmission in Vitro

Mayer, M L.

Abstract

This section investigates functional properties of excitatory amino acid receptors in the vertebrate CNS, utilizing electrophysiological and molecular biological techniques. Fast perfusion systems are used for concentration jump application of glutamate receptor selective agonists and antagonists to cells and membrane patches under voltage clamp. Preparations in use include primary cultures of hippocampal neurons and glial cells, and recombinant receptors expressed in transfected cells and oocytes. For NMDA receptors we have used agonist trapping during open channel block by 9-AA as a novel approach to estimate maximum open probability. Analysis of the molecular basis of AMPA receptor modulation by cyclothiazide is being investigated based on our observation that alternative splicing of the flip and flop variants, generated by use of alternative exons encoding 37 highly conserved amino acids, but which differ in core regions of only 4 + 1 amino acids, generates receptors with high and low sensitivity to cyclothiazide. Assay of cyclothiazide action on recombinant receptors, in which theses core residues are being exchanged, is being used to determine critical sites for allosteric modulation.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
• Type: Intramural Research (Z01)
• Project #: 1Z01HD000707-09
• Application #: 3756672
• Support Year: 9
• Fiscal Year: 1994

Institution

• Name: Eunice Kennedy Shriver National Institute of Child Health & Human Development
• Country: United States

Publications

Zhao, Huaying; Lomash, Suvendu; Chittori, Sagar et al. (2017) Preferential assembly of heteromeric kainate and AMPA receptor amino terminal domains. Elife 6:

Chaudhry, Charu; Plested, Andrew J R; Schuck, Peter et al. (2009) Energetics of glutamate receptor ligand binding domain dimer assembly are modulated by allosteric ions. Proc Natl Acad Sci U S A 106:12329-34

Vijayan, Ranjit; Plested, Andrew J R; Mayer, Mark L et al. (2009) Selectivity and cooperativity of modulatory ions in a neurotransmitter receptor. Biophys J 96:1751-60

Dolman, Nigel P; More, Julia C A; Alt, Andrew et al. (2007) Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 kainate receptor antagonists. J Med Chem 50:1558-70

Mayer, Mark L (2007) GRIK4 and the kainate receptor. Am J Psychiatry 164:1148

Plested, Andrew J R; Mayer, Mark L (2007) Structure and mechanism of kainate receptor modulation by anions. Neuron 53:829-41

Weston, Matthew C; Schuck, Peter; Ghosal, Alokesh et al. (2006) Conformational restriction blocks glutamate receptor desensitization. Nat Struct Mol Biol 13:1120-7

Mayer, Mark L; Ghosal, Alokesh; Dolman, Nigel P et al. (2006) Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci 26:2852-61

Yao, Yongneng; Mayer, Mark L (2006) Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J Neurosci 26:4559-66

Weston, Matthew C; Gertler, Christoph; Mayer, Mark L et al. (2006) Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate. J Neurosci 26:7650-8