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首页 » 生物研究 » J Gen Physiol:科学家揭示芋螺毒素抑制机体疼痛的分子机制

J Gen Physiol:科学家揭示芋螺毒素抑制机体疼痛的分子机制

来源:生物谷 2014-05-19 09:20

2014年5月16日 讯 /生物谷BIOON/ --海洋锥形蜗牛产生的毒液常用于捕杀猎物,毒液中含有芋螺毒素类的肽类,其中有些芋螺毒素可以在哺乳动物中作为止痛药来使用;近日刊登在国际杂志The Journal of General Physiology上的两篇研究论文中,来自墨尔本皇家理工学院的研究人员通过研究揭示了名为Vc1.1的芋螺毒素抑制疼痛的机制。

这项研究或可帮助科学家揭示天然毒素的止痛作用,并为开发合成性的Vc1.1用来治疗人类特殊的神经性疼痛提供了新的研究思路;神经性疼痛是一种常常和机体损伤并发的一种慢性疼痛,其往往让患者变的非常虚弱而且难以治疗,因此寻找有效的疗法治疗人类的神经性疼痛迫在眉睫。

神经性疼痛往往和神经元间信号传递的改变直接相关,神经元间信号的传递过程依赖于许多类型的压力门通钙通道(VGCCs),然而VGCCs对于调节正常的神经传递变的非常重要,利用其作用新型药物靶点来开发治疗神经性疼痛的药物将会带来一定的副作用。

此前研究中,研究者David Adams表示,Vc1.1可以抵御小鼠的神经性疼痛,Vc1.1并不是通过阻断VGCCs,其可以通过GABAb受体来抑制Cav2.2通道的信号传递。

如今,研究者通过研究表示,Vc1.1同样可以通过GABAb受体来抑制参与疼痛信号传递的神经元VGCCs,但是其中机制尚不清楚;本文的研究发现不仅可以帮助研究人员阐明Cav2.3通道的功能,而且可以鉴别出开发止痛剂的新型靶点。(生物谷Bioon.com)

Novel coupling is painless

Ann R. Rittenhouse

The first report that several neurotransmitters, including γ-aminobutyric acid (GABA), decreased neuronal action potential duration in dorsal root ganglia (DRG) neurons appeared more than 35 years ago (Dunlap and Fischbach, 1978). Dunlap and Fischbach (1978) realized that the effects of GABA could not occur via the ionotropic GABA receptor—at that time the only known GABA receptor—and that the target ion channel was most likely a voltage-gated calcium (CaV) channel, rather than a NaV or KV channel. They correctly concluded that another type of GABA receptor must exist, which we now know is the G protein–coupled GABA type B (GABAB) receptor. The modulated channel was later identified as the chick homologue of the N-type Ca2+ channel CaV2.2 (α1B) (Cox and Dunlap, 1992), one of three members of the CaV2 family. GABAB receptors in human and rodent sensory neurons and in various expression systems were shown subsequently to inhibit native N-current and recombinant CaV2.2 current, respectively (Raingo et al., 2007; Callaghan et al., 2008; Adams and Berecki, 2013). Inhibition primarily occurs by a voltage-dependent mechanism common to various neurotransmitters whereby Gβγ binds to CaV2.2 slowing channel opening, whereas positive voltage steps relieve this inhibition (Marchetti et al., 1986). The closely related P/Q-type (α1A) channel, CaV2.1, exhibits similar modulation by GABA (Mintz and Bean, 1993). The third member of the CaV2 family, CaV2.3 (α1E), is less susceptible to direct Gβγ modulation than the other two family members (Shekter et al., 1997). The revelation that mice with a deletion in either CaV2.2 or in CaV2.3 exhibited reduced neuropathic pain–like behavior, indicating that these channels participate in pain sensation signaling (Saegusa et al., 2000, 2001), sparked great interest in the regulation of CaV2 inhibition by GABAB receptors in DRG neurons. Astonishingly, however, the precise mechanism of GABAB receptor modulation of CaV2.3 channels has remained ill defined.

Differential Cav2.1 and Cav2.3 channel inhibition by baclofen and α-conotoxin Vc1.1 via GABAB receptor activation

Géza Berecki1, Jeffrey R. McArthur1, Hartmut Cuny1, Richard J. Clark2, and David J. Adams1

Neuronal Cav2.1 (P/Q-type), Cav2.2 (N-type), and Cav2.3 (R-type) calcium channels contribute to synaptic transmission and are modulated through G protein–coupled receptor pathways. The analgesic α-conotoxin Vc1.1 acts through γ-aminobutyric acid type B (GABAB) receptors (GABABRs) to inhibit Cav2.2 channels. We investigated GABABR-mediated modulation by Vc1.1, a cyclized form of Vc1.1 (c-Vc1.1), and the GABABR agonist baclofen of human Cav2.1 or Cav2.3 channels heterologously expressed in human embryonic kidney cells. 50 µM baclofen inhibited Cav2.1 and Cav2.3 channel Ba2+ currents by ∼40%, whereas c-Vc1.1 did not affect Cav2.1 but potently inhibited Cav2.3, with a half-maximal inhibitory concentration of ∼300 pM. Depolarizing paired pulses revealed that ∼75% of the baclofen inhibition of Cav2.1 was voltage dependent and could be relieved by strong depolarization. In contrast, baclofen or Vc1.1 inhibition of Cav2.3 channels was solely mediated through voltage-independent pathways that could be disrupted by pertussis toxin, guanosine 5′-[β-thio]diphosphate trilithium salt, or the GABABR antagonist CGP55845. Overexpression of the kinase c-Src significantly increased inhibition of Cav2.3 by c-Vc1.1. Conversely, coexpression of a catalytically inactive double mutant form of c-Src or pretreatment with a phosphorylated pp60c-Src peptide abolished the effect of c-Vc1.1. Site-directed mutational analyses of Cav2.3 demonstrated that tyrosines 1761 and 1765 within exon 37 are critical for inhibition of Cav2.3 by c-Vc1.1 and are involved in baclofen inhibition of these channels. Remarkably, point mutations introducing specific c-Src phosphorylation sites into human Cav2.1 channels conferred c-Vc1.1 sensitivity. Our findings show that Vc1.1 inhibition of Cav2.3, which defines Cav2.3 channels as potential targets for analgesic α-conotoxins, is caused by specific c-Src phosphorylation sites in the C terminus.

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