Methamphetamine decreases K(+) channel function in human fetal astrocytes by activating the trace amine-associated receptor type-1.
Methamphetamine decreases K(+) channel function in human fetal astrocytes by activating the trace amine-associated receptor type-1.
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DOI：
10.1111/jnc.14606
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发表时间：
2019-01
影响因子：
4.7
通讯作者：
Hu XT
中科院分区：
文献类型：
--
作者：
Dave S;Chen L;Yu C;Seaton M;Khodr CE;Al-Harthi L;Hu XT
甲基苯丙胺（冰毒）是一种强效且常被滥用的精神兴奋剂。甲基安非他明改变神经元和星形胶质细胞的活性；然而，其潜在的机制还没有被完全理解。在这里，我们使用全细胞贴片夹紧技术评估急性冰毒对人胎儿星形胶质细胞（hfa）的影响。我们发现hfa在膜去极化过程中通过Kv/Kv样通道表现出较大的电压门控K+流出（IKv），而在膜超极化过程中通过向内整流的Kir/Kir样通道表现出较小的K+内流（Ikir）。甲基安非他明在“娱乐性”（20 μM）或有毒/致命（100 μM）浓度下去极化静息膜电位（RMP）并抑制IKv/ kv样。这些变化与时间常数(T)的降低有关，并分别通过阻断双孔域K+ (K2P)/K2P-和Kv/Kv-通道来模拟。甲基苯丙胺也会减少IKir/ kir样，但只有在有毒/致命的水平。鉴于甲基安非他明是微量胺相关受体1型（TAAR1）和TAAR1偶联cAMP/cAMP活化蛋白激酶（PKA）级联的有效激动剂，我们进一步评估了甲基安非他明对K+外排的影响是否通过这一途径介导。我们发现用N-（3-乙氧基苯基）-4-（1-吡咯烷基）-3-（三氟甲基）苯甲酰胺（EPPTB）拮抗TAAR1可逆转甲氧基诱导的IKv/ kv样抑制；H89抑制PKA活性可消除甲基安非他明对IKv/Kv- like的抑制作用。拮抗TAAR1也可能减弱冰毒诱导的RMP去极化。在hfa中未检测到电压门控Ca2+电流。这些新发现表明，甲基安非他明通过促进TAAR1/Gs/cAMP/PKA级联和改变Kv/Kv样通道门控动力学来抑制IKv/Kv样通道，但通过其他途径降低hfa中K2P/K2P样通道活性。通过K2P/K2P样通道和Kv/Kv样通道诱导的星形细胞K+外排减少降低了细胞外K+水平，因此这种减少可能导致周围神经元兴奋性降低。
Methamphetamine (Meth) is a potent and commonly abused psychostimulant. Meth alters neuron and astrocyte activity; yet the underlying mechanism(s) is not fully understood. Here we assessed the impact of acute Meth on human fetal astrocytes (HFAs) using whole-cell patch-clamping. We found that HFAs displayed a large voltage-gated K+ efflux (IKv) through Kv/Kv- like channels during membrane depolarization, and a smaller K+ influx (Ikir) via inward-rectifying Kir/Kir-like channels during membrane hyperpolarization. Meth at a ‘recreational’ (20 μM) or toxic/fatal (100 μM) concentration depolarized resting membrane potential (RMP) and suppressed IKv/Kv-like. These changes were associated with a decreased time constant (T), and mimicked by blocking the two-pore domain K+ (K2P)/K2P- like and Kv/Kv-like channels, respectively. Meth also diminished IKir/Kir-like, but only at toxic/fatal levels. Given that Meth is a potent agonist for the trace amine-associated receptor type-1 (TAAR1), and TAAR1-coupled cAMP/cAMP-activated protein kinase (PKA) cascade, we further evaluated whether the Meth impact on K+ efflux was mediated by this pathway. We found that antagonizing TAAR1 with N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) reversed Meth-induced suppression of IKv/Kv-like; and inhibiting PKA activity by H89 abolished Meth effects on suppressing IKv/Kv- like. Antagonizing TAAR1 might also attenuate Meth-induced RMP depolarization. Voltage-gated Ca2+ currents were not detected in HFAs. These novel findings demonstrate that Meth suppresses IKv/Kv-like by facilitating the TAAR1/Gs/cAMP/PKA cascade and altering the kinetics of Kv/Kv-like channel gating, but reduces K2P/K2P-like channel activity through other pathway(s), in HFAs. Given that Meth-induced decrease in astrocytic K+ efflux through K2P/K2P-like and Kv/Kv-like channels reduces extracellular K+ levels, such reduction could consequently contribute to a decreased excitability of surrounding neurons.
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影响因子：
5.3
作者：
Dong, Y;Cooper, D;White, FJ
通讯作者：
White, FJ
安非他明、3,4-亚甲二氧基甲基苯丙胺、麦角酸二乙酰胺和儿茶酚胺神经递质的代谢物是大鼠微量胺受体的激动剂
影响因子：
3.6
作者：
Bunzow, JR;Sonders, MS;Grandy, DK
通讯作者：
Grandy, DK
影响因子：
2.5
作者：
Kiely, Elizabeth;Lee, C. Jeff;Marinetti, Laureen
通讯作者：
Marinetti, Laureen
影响因子：
15.9
作者：
Giaume, C;McCarthy, KD
通讯作者：
McCarthy, KD
DOI：
10.1016/b978-0-12-420118-7.00001-9
发表时间：
2014
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Beardsley, Patrick M;Hauser, Kurt F
通讯作者：
Hauser, Kurt F