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首页> 外文期刊>Journal of Neurophysiology >Rat group I metabotropic glutamate receptors inhibit neuronal Ca2+ channels via multiple signal transduction pathways in HEK 293 cells.
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Rat group I metabotropic glutamate receptors inhibit neuronal Ca2+ channels via multiple signal transduction pathways in HEK 293 cells.

机译：大鼠I组代谢型谷氨酸受体通过HEK 293细胞中的多种信号转导途径抑制神经元Ca2 +通道。

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We have shown previously that metabotropic glutamate receptors with group I-like pharmacology couple to N-type and P/Q-type calcium channels in acutely isolated cortical neurons using G proteins most likely belonging to the Gi/Go subclass. To better understand the potential mechanisms forming the basis for group I mGluR modulation of voltage-gated calcium channels in the CNS, we have examined the ability of specific mGluRs to couple to neuronal N-type (alpha1B-1/alpha2delta/beta1b) and P/Q-type (alpha1A-2/alpha2delta/beta1b) voltage-gated calcium channels in an HEK 293 heterologous expression system. Using the whole cell patch-clamp technique where intracellular calcium is buffered to low levels, we have shown that group I receptors inhibit both N-type and P/Q-type calcium channels in a voltage-dependent fashion. Similar to our observations in cortical neurons, this voltage-dependent inhibition is mediated almost entirely by N-ethylmaleimide (NEM)-sensitive heterotrimeric G proteins, strongly suggesting that these receptors can use Gi/Go-like G proteins to couple to N-type and P/Q-type calcium channels. However, inconsistent with the apparent NEM sensitivity of group I modulation of calcium channels, modulation of N-type channels in group I mGluR-expressing cells was only partially sensitive to pertussis toxin (PTX), indicating the potential involvement of both PTX-sensitive and -resistant G proteins. The PTX-resistant modulation was voltage dependent and entirely resistant to NEM and cholera toxin. A time course of treatment with PTX revealed that this toxin caused group I receptors to slowly shift from using a primarily NEM-sensitive G protein to using a NEM-resistant form. The PTX-induced switch from NEM-sensitive to -resistant modulation was also dependent on protein synthesis, indicating some reliance on active cellular processes. In addition to these voltage-dependent pathways, perforated patch recordings on group I mGluR-expressing cells indicate that another slowly developing, calcium-dependent form of modulation for N-type channels may be seen when intracellular calcium is not highly buffered. We conclude that group I mGluRs can modulate neuronal Ca2+ channels using a variety of signal transduction pathways and propose that the relative contributions of different pathways may exemplify the diversity of responses mediated by these receptors in the CNS.
机译：先前我们已经证明，具有I类药理作用的代谢型谷氨酸受体与使用G蛋白最可能属于Gi / Go亚类的G蛋白急性分离的皮质神经元中的N型和P / Q型钙通道耦合。为了更好地了解构成中枢神经系统中电压门控钙通道的I组mGluR调节基础的潜在机制，我们研究了特定mGluR与神经元N型（alpha1B-1 / alpha2delta / beta1b）和P偶联的能力。 HEK 293异源表达系统中的/ Q型（alpha1A-2 / alpha2delta / beta1b）电压门控钙通道。使用将细胞内钙缓冲至低水平的全细胞膜片钳技术，我们已显示I组受体以电压依赖性方式抑制N型和P / Q型钙通道。与我们在皮层神经元中的观察相似，这种电压依赖性抑制作用几乎完全由对N-乙基马来酰亚胺（NEM）敏感的异三聚体G蛋白介导，强烈暗示这些受体可以使用Gi / Go-like G蛋白偶联至N型和P / Q型钙通道。然而，与I组钙通道调节的明显NEM敏感性不一致，I组mGluR表达细胞中N型通道的调节仅对百日咳毒素（PTX）部分敏感，表明PTX敏感性和PTX敏感性都可能参与。抗性G蛋白。耐PTX的调制依赖于电压，并且完全耐NEM和霍乱毒素。用PTX治疗的时间过程表明，该毒素导致I组受体从使用主要为NEM敏感的G蛋白缓慢转变为使用耐NEM的形式。 PTX诱导的从NEM敏感到耐药的转换也取决于蛋白质的合成，表明对活性细胞过程的依赖。除这些电压依赖性途径外，在第I组表达mGluR的细胞上打孔的斑片记录表明，当细胞内钙的缓冲水平不高时，可以看到另一种缓慢发展的钙依赖性形式的N型通道调节。我们得出的结论是，第I组mGluRs可以使用多种信号转导途径调节神经元Ca2 +通道，并提出不同途径的相对作用可以例证这些受体在CNS中介导的反应的多样性。

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