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α-肾上腺素能受体-PKC-Pyk2-Src 信号通路增强了啮齿动物的 L 型钙通道 Ca1.2 活性和长时程增强。

α-Adrenergic receptor-PKC-Pyk2-Src signaling boosts L-type Ca channel Ca1.2 activity and long-term potentiation in rodents.

机构信息

Department of Pharmacology, University of California, Davis, United States.

Department of Pharmacology, University of Iowa, Iowa City, United States.

出版信息

Elife. 2023 Jun 20;12:e79648. doi: 10.7554/eLife.79648.

DOI:10.7554/eLife.79648
PMID:37338965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10325713/
Abstract

The cellular mechanisms mediating norepinephrine (NE) functions in brain to result in behaviors are unknown. We identified the L-type Ca channel (LTCC) Ca1.2 as a principal target for G-coupled α-adrenergic receptors (ARs). αAR signaling increased LTCC activity in hippocampal neurons. This regulation required protein kinase C (PKC)-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with Ca1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of Ca1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by αAR and formation of a signaling complex with PKC, Pyk2, and Src suggests that Ca1.2 is a central conduit for signaling by NE. Indeed, a form of hippocampal long-term potentiation (LTP) in young mice requires both the LTCC and αAR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of Ca1.2 activity via αAR-Pyk2-Src signaling regulates synaptic strength.

摘要

介导去甲肾上腺素 (NE) 在大脑中发挥作用并导致行为的细胞机制尚不清楚。我们确定 L 型钙通道 (LTCC) Ca1.2 是 G 蛋白偶联 α 肾上腺素能受体 (AR) 的主要靶标。αAR 信号增加海马神经元中的 LTCC 活性。这种调节需要蛋白激酶 C (PKC) 介导的酪氨酸激酶 Pyk2 和下游的Src 的激活。Pyk2 和 Src 与 Ca1.2 相关。在模型神经内分泌 PC12 细胞中，PKC 的刺激诱导 Ca1.2 的酪氨酸磷酸化，这种修饰被 Pyk2 和 Src 的抑制所消除。αAR 上调 LTCC 活性并与 PKC、Pyk2 和 Src 形成信号复合物表明 Ca1.2 是 NE 信号的中心途径。事实上，年轻小鼠海马体的一种形式的长时程增强 (LTP) 需要 LTCC 和 αAR 刺激。抑制 Pyk2 和 Src 阻断了这种 LTP，表明通过 αAR-Pyk2-Src 信号增强 Ca1.2 活性调节突触强度。

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