کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8517332 | 1556586 | 2018 | 22 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Spontaneous activity, singly bound states and the impact of alpha1Phe64 mutation on GABAAR gating in the novel kinetic model based on the single-channel recordings
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کلمات کلیدی
FBSPCMVHEPESALACysLEUHEK-293tetraethylammonium chloridecDNA - cDNATEA-Cl - TEA-CLopen probability - احتمال باز بودنγ-aminobutyric acid - اسید γ-آمینوبوتیریکcomplementary deoxyribonucleic acid - اسید دز اکسید ریبونوکلئیک مکملmean open time - به معنی زمان باز استintermediate states - حالت های متوسطCritical time - زمان انتقادیfetal bovine serum - سرم جنین گاوhuman embryonic kidney cell line - سلول انسانی جنین انسانspontaneous activity - فعالیت خود به خودیOuter diameter - قطر خارجیinner diameter - قطر داخلیpen/strep - قلم / استرپKinetic model - مدل جنبشیPopen - پاپنGABAA receptor - گیرنده GABAA یا گیرنده گابا
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
GABAA receptor is the primary mediator of inhibition in the adult mammalian brain. Our recent studies revealed that a classic gating scheme for GABAAR needed to be updated with an intermediate step (flipping) and that the α1Phe64 mutation at the GABA binding site affects this transition. However, description of flipping at the single-channel level remains incomplete. In particular, its role in singly-bound and spontaneous activity remains unknown. We have performed thus single-channel recordings over wide range of agonist concentration for wild-type α1β2γ2L receptors and α1Phe64 mutants. For WT receptors we observed relatively frequent brief spontaneous openings which were also present at low [GABA]. However, closed times distributions for spontaneous activity and at low [GABA] were clearly different indicating that a proportion of short-lived openings were due to liganded, most likely singly bound receptors. Increasing [GABA] resulted in prolongation of bursts and increased occurrence of bursts with long openings and short closures. Mutations of α1Phe64 residue dramatically affected the open and closed time distributions at high and saturating [GABA], especially in the case of cysteine mutants. However, this mutation weakly affected spontaneous or singly bound activity. Model fitting of our single-channel data led us to propose a novel and, to our knowledge, most complete GABAAR kinetic model in which flipping occurs in singly and doubly bound states. However, spontaneous activity did not reveal involvement of flipping. Moreover, we report that α1Phe64 mutation affects not only the flipping but also the opening/closing transitions indicating its generalized impact on the receptor gating.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 131, 15 March 2018, Pages 453-474
Journal: Neuropharmacology - Volume 131, 15 March 2018, Pages 453-474
نویسندگان
Magdalena Kisiel, Magdalena Jatczak, Marek Brodzki, Jerzy W. Mozrzymas,