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1.
Nat Neurosci ; 15(7): 970-8, 2012 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-22660477

RESUMO

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABA(B) receptor is a G protein-coupled receptor central to mammalian brain function. Malfunction of GABA(B) receptor has been implicated in several neurological disorders. GABA(B) receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimeric interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABA(B) receptor that is unique to the GABAergic system.


Assuntos
Líquido Extracelular/química , Receptores de GABA-B/química , Receptores de GABA-B/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/fisiologia , Células HEK293 , Humanos , Dados de Sequência Molecular , Conformação Proteica , Estrutura Terciária de Proteína/genética , Receptores de GABA-B/genética , Relação Estrutura-Atividade
2.
Channels (Austin) ; 1(4): 273-80, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18708744

RESUMO

Inherited mutations of SCN5A, the gene that encodes Na(V)1.5, the alpha subunit of the principle voltage-gated Na(+) channel in the heart, cause congenital Long QT Syndrome variant 3 (LQT-3) by perturbation of channel inactivation. LQT-3 mutations induce small, but aberrant, inward current that prolongs the ventricular action potential and subjects mutation carriers to arrhythmia risk dictated in part by the biophysical consequences of the mutations. Most previously investigated LQT-3 mutations are associated with increased arrhythmia risk during rest or sleep. Here we report a novel LQT-3 mutation discovered in a pediatric proband diagnosed with LQTS but who experienced cardiac events during periods of mild exercise as well as rest. The mutation, which changes a single amino acid (S1904L) in the Na(V)1.5 carboxy terminal domain, disrupts the channel inactivation gate complex and promotes late Na(+) channel currents, not by promoting a bursting mode of gating, but by increasing the propensity of the channel to reopen during prolonged depolarization. Incorporating a modified version of the Markov model of the Na(V)1.5 channel into a mathematical model of the human ventricular action potential predicts that the biophysical consequences of the S1904L mutation result in action potential prolongation that is seen for all heart rates but, in contrast to other previously-investigated LQT-3 mutant channels, is most pronounced at fast rates resulting in a drastic reduction in the cells ability to adapt APD to heart rate.


Assuntos
Arritmias Cardíacas/genética , Sistema de Condução Cardíaco/metabolismo , Ativação do Canal Iônico/genética , Síndrome do QT Longo/genética , Proteínas Musculares/genética , Mutação , Canais de Sódio/genética , Sódio/metabolismo , Potenciais de Ação , Substituição de Aminoácidos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Criança , Eletrocardiografia , Predisposição Genética para Doença , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Humanos , Cinética , Síndrome do QT Longo/complicações , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Masculino , Cadeias de Markov , Modelos Cardiovasculares , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5 , Linhagem , Fenótipo , Conformação Proteica , Canais de Sódio/química , Canais de Sódio/metabolismo
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