ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice
| Autor: | Gary A. Sulikowski, C. David Weaver, Bende Zou, Emily Days, Liya Yang, Jerod S. Denton, Greg Sliwoski, Conrado Pascual, Adam Malik, Colleen M. Niswender, Ian M. Romaine, Ryan D. Morrison, Craig W. Lindsley, Xinmin Simon Xie, Kristian Kaufmann, J. Scott Daniels, Yu Du |
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| Rok vydání: | 2013 |
| Předmět: |
Patch-Clamp Techniques
Physiology G protein Cognitive Neuroscience Drug Evaluation Preclinical Receptors Metabotropic Glutamate Biochemistry Mice Seizures Animals Humans Calcium Signaling G protein-coupled inwardly-rectifying potassium channel Patch clamp Ion channel Calcium signaling Electroshock Dose-Response Relationship Drug Molecular Structure urogenital system Chemistry Inward-rectifier potassium ion channel Activator (genetics) Phenylurea Compounds Valproic Acid Cell Biology General Medicine Recombinant Proteins Potassium channel High-Throughput Screening Assays Rats HEK293 Cells G Protein-Coupled Inwardly-Rectifying Potassium Channels Microsomes Liver Pentylenetetrazole Pyrazoles Anticonvulsants Neuroscience Injections Intraperitoneal |
| Zdroj: | ACS Chemical Neuroscience. 4:1278-1286 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/cn400062a |
| Popis: | The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications. |
| Databáze: | OpenAIRE |
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