کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5813167 | 1556606 | 2016 | 45 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanism of direct Cav2.2 channel block by the κ-opioid receptor agonist U50488H
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کلمات کلیدی
HEPESEGTAHEK293GPCRCaV1.3Human embryonic kidney 293 cellsU50488Hadenosine 5′-triphosphate - آدنوزین 5'-تری فسفاتATP - آدنوزین تری فسفات یا ATPUse-dependent block - استفاده از بلوک وابستهTetraethylammonium - تترا اتیل آمونیومholding potential - داشتن پتانسیلInactivation - غیر فعال کردنTEA - چایkappa-opioid receptor - گیرنده کاپا اپیوئیدG protein-coupled receptor - گیرندههای جفتشونده با پروتئین جی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
U50488H is a benzeneacetamide κ-opioid receptor (κ-OR) agonist analgesic, widely used for investigating the pharmacology of G protein-coupled κ-ORs. However, U50488H is also known to directly block various voltage-gated ion channels in a G protein-independent manner. We investigated the direct actions of U50488H on various high voltage-activated (HVA) and low voltage-activated (LVA) neuronal Ca2+ channels heterologously expressed in human embryonic kidney (HEK293) cells. U50488H inhibited HVA rat Cav1.3 (rCav1.3), human Cav2.1 (hCav2.1), hCav2.2, hCav2.3, and LVA hCav3.1 and hCav3.2 channels in a concentration-dependent manner, with similar potencies characterised with half-maximal inhibitory concentration (IC50) values of â¼30 μM. U50488H concentrations causing direct Cav inhibition are typically >100 times higher than those producing κ-OR activation. Investigation of the mechanism of U50488H block of the Cav2.2 channel revealed that U50488H interacted with all major kinetic states of the channel â resting, open, and inactivated. U50488H did not affect the voltage dependence of activation but shifted the steady-state inactivation curve by â¼11 mV to more hyperpolarized potentials. U50488H also increased the rate of Ba2+ current inactivation during a step depolarization and significantly delayed recovery from slow inactivation, compared with control. Cav2.2 current inhibition was frequency dependent during repetitive step depolarization at 1 Hz and 3 Hz, consistent with use-dependent block. In summary, our results suggest that preferential interaction of U50488H with inactivated Cav2.2 channels significantly contributes to reduced Cav2.2 channel availability and slow recovery form inactivation. We conclude that U50488H non-selectively blocks heterologously expressed neuronal HVA and LVA Cav channels in the absence of κ-ORs. This cross-reactivity also suggests potentially common U50488H binding motifs across Cav channel targets.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 109, October 2016, Pages 49-58
Journal: Neuropharmacology - Volume 109, October 2016, Pages 49-58
نویسندگان
Géza Berecki, Leonid Motin, David J. Adams,