title: EPAC inhibition of SUR1 receptor increases glutamate release and seizure vulnerability.
abstract: EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified. Here we show that EPAC binds directly to the intracellular loop of an ATP-sensitive potassium (KATP) channel type-1 sulfonylurea receptor (SUR1) receptor consisting of amino acids 859-881 (SUR1(859-881)). Ablation of EPAC or expression of SUR1(859-881), which intercepts EPAC-SUR1 binding, increases the open probability of KATP channels consisting of the Kir6.1 subunit and SUR1. Opening of KATP channels inhibits glutamate release and reduces seizure vulnerability in adult mice. Therefore, EPAC interaction with SUR1 controls seizure susceptibility and possibly acts via regulation of glutamate release.
authors.affiliation: Key Laboratory of Neurological Disease, Ministry of Education, Huazhong University of Science and Technology Tongji Medical College, Wuhan, 430030 China.
authors.forename: Kunpeng
authors.initials: K
authors.lastname: Zhao
authors.forename: Ruojian
authors.initials: R
authors.lastname: Wen
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Pei
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: You
authors.initials: Y
authors.lastname: Shang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bazan
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011336:Probability; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: C482601:Epac protein, mouse; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D020662:Guanine Nucleotide Exchange Factors; D054086:KATP Channels; D011810:Quinoxalines; C486707:Rapgef4 protein, mouse; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D007608:Kainic Acid; D001640:Bicuculline