Multiple actions of propofol on αβγ and αβδ GABAA receptors
Multiple actions of propofol on αβγ and αβδ GABAA receptors
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DOI：
10.1124/mol.104.003426
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发表时间：
2004-12-01
影响因子：
3.6
通讯作者：
Macdonald, RL
中科院分区：
文献类型：
--
作者：
Feng, HJ;Macdonald, RL
大脑中的GABA(A)受体主要由α-β-氨基丁酸和α-β-β-氨基丁酸组成。已有研究提出，α-β受体介导时相抑制，而α-倍他受体则介导紧张性抑制。异丙酚(2，6-二异丙基苯酚)是一种广泛使用的麻醉药，其作用主要通过调节GABA(A)受体发挥作用，然而，异丙酚对α-受体和α-受体动力学特性的影响尚不清楚。我们用编码大鼠α1、α6、β3、γ2L或增量亚单位的cDNA转染人胚胎肾(HEK293T)细胞，并进行全细胞膜片钳记录以探讨这一问题。异丙酚(3um)对α1β3γ2L和α6β3γ2L受体的GABA量效曲线最大电流的增加作用相似，但对α1β3Delta和α6β3Delta受体的最大电流有不同程度的增加，且α1β3Delta的增加幅度大于α6β3Delta受体。异丙酚(10微米)对α1β3γ2L和α6β3γ2L受体电流有类似的影响，峰电流不变，脱敏程度降低，失活时间延长。异丙酚可增强α1β3和α6β3受体的峰电流，但对α1β3受体的增强作用更强。异丙酚不能改变这两种异构体的脱敏作用。异丙酚不改变α1β3受体电流的失活率，但减缓α6β3受体电流的失活。异丙酚可降低含γ2L亚基受体的脱敏作用和延长失活时间，增加或延长含Delta亚基受体的失活时间，提示异丙酚增强时相和紧张性抑制作用可能与其在脑内的麻醉作用有关。
GABA(A) receptors are predominantly composed of alphabetagamma and alphabetadelta isoforms in the brain. It has been proposed that alphabetagamma receptors mediate phasic inhibition, whereas alphabetadelta receptors mediate tonic inhibition. Propofol (2,6-di-isopropylphenol), a widely used anesthetic drug, exerts its effect primarily by modulating GABA(A) receptors; however, the effects of propofol on the kinetic properties of alphabetagamma and alphabetadelta receptors are uncertain. We transfected human embryonic kidney (HEK293T) cells with cDNAs encoding rat alpha1, alpha6, beta3, gamma2L, or delta subunits and performed whole-cell patch-clamp recordings to explore this issue. Propofol (3 muM) increased GABA concentration-response curve maximal currents similarly for both alpha1beta3gamma2L and alpha6beta3gamma2L receptors, but propofol increased those for alpha1beta3delta and alpha6beta3delta receptors differently, the increase being greater for alpha1beta3delta than for alpha6beta3delta receptors. Propofol (10 muM) produced similar alterations in alpha1beta3gamma2L and alpha6beta3gamma2L receptor currents when using a preapplication protocol; peak currents were not altered, desensitization was reduced, and deactivation was prolonged. Propofol enhanced peak currents for both alpha1beta3delta and alpha6beta3delta receptors, but the enhancement was greater for alpha1beta3delta receptors. Desensitization of these two isoforms was not modified by propofol. Propofol did not alter the deactivation rate of alpha1beta3delta receptor currents but did slow deactivation of alpha6beta3delta receptor currents. The findings that propofol reduced desensitization and prolonged deactivation of gamma2L subunit-containing receptors and enhanced peak currents or prolonged deactivation of delta subunit-containing receptors suggest that propofol enhancement of both phasic and tonic inhibition may contribute to its anesthetic effect in the brain.