Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.
Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.
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DOI：
10.1113/jp283433
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发表时间：
2022-10
影响因子：
5.5
通讯作者：
Lei, Saobo
中科院分区：
文献类型：
--
作者：
Boyle, Cody A.;Hu, Binqi;Quaintance, Kati L.;Mastrud, Morgan R.;Lei, Saobo
速激肽肽包括P物质（SP）、神经激肽A（NKA）和神经激肽B（NKB），它们分别与三种G蛋白偶联的神经激肽受体NK 1 R、NK 2 R和NK 3 R相互作用。尽管已经在基底外侧杏仁核（BLA）中检测到高密度的NK 3R，但尚未确定NK 3R在该脑区域中的功能。我们发现，通过应用选择性激动剂senktide激活NK 3Rs，持续兴奋BLA主要神经元。NK 3R引起的BLA神经元兴奋通过激活非选择性阳离子通道和抑制内向整流K+（Kir）通道介导。在选择性通道阻断剂和敲除小鼠中，我们进一步发现NK 3R激活通过抑制G蛋白激活的内向整流K+（GIRK）通道和激活TRPC 4和TRPC 5通道来兴奋BLA神经元。NK 3Rs的作用需要磷脂酶Cβ（PLCβ）的作用，但不依赖于胞内Ca ~（2+）释放和蛋白激酶C。PLCβ介导的4，5-二磷酸磷脂酰肌醇（PIP 2）耗竭参与了NK 3R诱导的BLA神经元兴奋。将senktide微量注射到大鼠的BLA中增强了恐惧增强的惊吓（FPS），并且这种效应被预先注射选择性NK 3R拮抗剂SB 218795阻断，表明BLA中NK 3R的激活增加了FPS。我们进一步发现TRPC 4/5和GIRK通道参与了NK 3R诱导的FPS易化。我们的研究结果提供了一个细胞和分子机制，NK 3R激活兴奋BLA神经元和增强FPS。神经激肽-B（NKB）是速激肽肽家族的成员，在中枢脑回路中充当神经递质或神经调质，而杏仁核是该肽的重要靶点。NKB激活神经激肽-3受体（NK 3R），其是通过PLCβ途径进行信号传导的Gq/11偶联受体。虽然在基底外侧杏仁核（BLA）中检测到高密度的NK 3R，但尚未确定NK 3R在该脑区中的激活功能。我们发现，激活NK 3Rs通过激活TRPC 4/5通道和抑制GIRK型内向整流K+通道来兴奋BLA主神经元。PLCβ介导的4，5-二磷酸磷脂酰肌醇（PIP 2）耗竭是NK 3R诱导的BLA神经元兴奋的原因。BLA中NK 3R的激活通过TRPC 4/5通道的激活和GIRK通道的抑制显著增加恐惧增强的惊吓反应。我们的研究结果提供了一个细胞和分子机制来解释NK 3R引起的恐惧反应的增强。
The tachykinin peptides include substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), which interact with three G-protein-coupled neurokinin receptors, NK1Rs, NK2Rs, and NK3Rs, respectively. Whereas high densities of NK3Rs have been detected in the basolateral amygdala (BLA), the functions of NK3Rs in this brain region have not been determined. We found that activation of NK3Rs by application of the selective agonist, senktide, persistently excited BLA principal neurons. NK3R-elicited excitation of BLA neurons was mediated by activation of a nonselective cation channel and depression of the inwardly rectifying K+ (Kir) channels. With selective channel blockers and knockout mice, we further showed that NK3R activation excited BLA neurons by depressing the G protein-activated inwardly rectifying K+ (GIRK) channels and activating TRPC4 and TRPC5 channels. The effects of NK3Rs required the functions of phospholipase Cβ (PLCβ), but were independent of intracellular Ca2+ release and protein kinase C. PLCβ-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) was involved in NK3R-induced excitation of BLA neurons. Microinjection of senktide into the BLA of rats augmented fear-potentiated startle (FPS) and this effect was blocked by prior injection of the selective NK3R antagonist, SB 218795, suggesting that activation of NK3Rs in the BLA increased FPS. We further showed that TRPC4/5 and GIRK channels were involved in NK3R-elicited facilitation of FPS. Our results provide a cellular and molecular mechanism whereby NK3R activation excites BLA neurons and enhances FPS. Neurokinin-B (NKB) is a member of the tachykinin family of peptides that act as a neurotransmitter or neuromodulator in central brain circuits and the amygdala is an important target for this peptide. NKB activates the neurokinin-3 receptors (NK3Rs) which are Gq/11-coupled receptors signaling through the PLCβ pathway. While high densities of NK3Rs have been detected in the basolateral amygdala (BLA), the functions of NK3R activation in this brain region have not been determined. We found that activation of NK3Rs excited BLA principal neurons by activating TRPC4/5 channels and depressing the GIRK type of the inwardly rectifying K+ channels. PLCβ-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) was responsible for NK3R-induced excitation of BLA neurons. Activation of NK3Rs in the BLA significantly increased the fear-potentiated startle responses via activation of TRPC4/5 channels and suppression of GIRK channels. Our results provide a cellular and molecular mechanism to explain NK3R-elicited augmentation of fear responses.