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首页> 外文期刊>Cellular Signalling >Ghrelin suppresses Purkinje neuron P-type Ca~(2+) channels via growth hormone secretagogue type 1a receptor, the βγ subunits of Go-protein, and protein kinase A pathway
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Ghrelin suppresses Purkinje neuron P-type Ca~(2+) channels via growth hormone secretagogue type 1a receptor, the βγ subunits of Go-protein, and protein kinase A pathway

机译：Ghrelin通过生长激素促分泌素1a型受体，Go蛋白的βγ亚基和蛋白激酶A途径抑制Purkinje神经元P型Ca〜（2+）通道

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摘要

Although ghrelin receptors have been demonstrated to be widely expressed in the central nervous system and peripheral tissues of mammals, it is still unknown whether ghrelin functions in cerebellar Purkinje neurons. In this study, we identified a novel functional role for ghrelin in modulating P-type Ca~(2+) channel (P-type channel) currents (I_(Ba)) as well as action-potential firing in rat Purkinje neurons. Our results show that ghrelin at 0.1 μM reversibly decreased IBa by ~32.3%. This effect was growth hormone secretagogue receptor 1a (GHS-R1a)- dependent and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Intracellular application of GDP-β-S and pretreatment with pertussis toxin abolished the inhibitory effects of ghrelin. Dialysis of cells with the peptide QEHA (but not the scrambled peptide SKEE), and a selective antibody raised against the G-proteinαo subunit both blocked the ghrelin-induced response. Ghrelin markedly increased protein kinase A (PKA) activity, and intracellular application of PKI 5-24 aswell as pretreatment of the cellswith the PKA inhibitor KT-5720 abolished ghrelin-induced IBa decrease, while inhibition of PKC had no such effects. At the cellular level, ghrelin induced a significant increase in action-potential firing, and blockade of GHS-R1a by BIM- 28163 abolished the ghrelin-induced hyperexcitability. In summary, these results suggest that ghrelin markedly decreases I_(Ba) via the activation of GHS-R1a, which is coupled sequentially to the activities of G_o-protein βγ subunits and the downstream PKA pathway. This could contribute to its physiological functions, including the spontaneous firing of action potentials in cerebellar Purkinje neurons.
机译：尽管ghrelin受体已被证明在哺乳动物的中枢神经系统和周围组织中广泛表达，但仍不清楚ghrelin是否在小脑浦肯野神经元中起作用。在这项研究中，我们确定了生长素释放肽在调节大鼠Purkinje神经元中的P型Ca〜（2+）通道（P_channel）电流（I_（Ba））以及动作电位激发中的新型功能作用。我们的结果表明，0.1μM的生长素释放肽可逆地使IBa降低约32.3％。该作用是生长激素促分泌素受体1a（GHS-R1a）依赖性的，并且与失活的电压依赖性的超极化转变有关。细胞内施用GDP-β-S并用百日咳毒素预处理可消除ghrelin的抑制作用。用肽QEHA（而不是混乱的肽SKEE）透析细胞，以及针对G蛋白αo亚基的选择性抗体均阻断了生长素释放肽诱导的反应。 Ghrelin显着增加了蛋白激酶A（PKA）的活性，在细胞内施用PKI 5-24以及用PKA抑制剂KT-5720预处理细胞均消除了Ghrelin诱导的IBa降低，而对PKC的抑制则无此作用。在细胞水平上，ghrelin引起动作电位放电的显着增加，而BIM- 28163对GHS-R1a的阻断消除了ghrelin引起的过度兴奋性。总之，这些结果表明，生长素释放肽通过GHS-R1a的激活显着降低I_（Ba），GHS-R1a依次与G_o-蛋白βγ亚基的活性和下游的PKA途径偶联。这可能有助于其生理功能，包括小脑浦肯野神经元中动作电位的自发放电。

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