title: Photo-antagonism of the GABAA receptor.
abstract: Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation.
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors: Martin
authors: M
authors: Mortensen
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: Favaad
authors: F
authors: Iqbal
authors: Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London WC1E 7HX, UK.
authors: Arun P
authors: AP
authors: Pandurangan
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors: Saad
authors: S
authors: Hannan
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: Rosemary
authors: R
authors: Huckvale
authors: Institute of Structural and Molecular Biology, Crystallography/Department of Biological Sciences, Birkbeck College, University of London, London WC1E 7HX, UK.
authors: Maya
authors: M
authors: Topf
authors: Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
authors: James R
authors: JR
authors: Baker
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors: Trevor G
authors: TG
authors: Smart
mesh_terms: D000704:Analysis of Variance; D001921:Brain / Q000502:physiology*; D018756:GABA Antagonists / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011724:Pyridazines; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D013569:Synapses / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C049853:gabazine