Subunit-specific photocontrol of glycine receptors by azobenzene-nitrazepam photoswitcher
| Autor: | Piotr Bregestovski, Daniel Wutz, Mercedes Alfonso-Prieto, Alexandre M. J. Gomila, Elena Petukhova, Daria Ponomareva, Alba Nin-Hill, Elvira Mukhametova, Galyna Maleeva, Burkhard König, Pau Gorostiza, Karin Rustler |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Farmacologia
hypoglossal motoneurons Patch-Clamp Techniques Neuronal Excitability Drug action Inhibitory postsynaptic potential Mice Receptors Glycine medicine Animals photopharmacology Channel blocker ddc:610 Hyperekplexia Nitrazepam Receptor Glycine receptor Pharmacology GABAA receptor Chemistry glycine receptors General Neuroscience General Medicine patch-clamp brain slices molecular modelling Transmembrane domain Amino acids Aminoàcids medicine.symptom Azo Compounds Neuroscience Research Article: New Research |
| Zdroj: | Juelich Shared Electronic Resources Recolector de Ciencia Abierta, RECOLECTA PubMed Central Diposit Digital de la Universitat de Barcelona ZENODO UnpayWall ORCID Microsoft Academic Graph eNeuro eNeuro 8(1), ENEURO.0294-20.2020 (2021). doi:10.1523/ENEURO.0294-20.2020 Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | Visual Abstract Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy, and autism. Here, we demonstrate that Azo-NZ1 blocks in a UV-dependent manner the activity of α2 GlyRs (GlyR2), while being barely active on α1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2’ position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit-specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing “fetal” GlyR2 to “adult” GlyR1 receptors. |
| Databáze: | OpenAIRE |
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