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KLHL1基因缺失导致下丘脑POMC神经元兴奋性增高以及对瘦素无电反应。

Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin.

作者信息

Perissinotti Paula P, Martínez-Hernández Elizabeth, He Yungui, Koob Michael D, Piedras-Rentería Erika S

机构信息

Cell and Molecular Physiology Department and Neuroscience Division of the Cardiovascular Research Institute, Loyola University Chicago, Maywood, IL, United States.

Institute for Translational Neuroscience and Department of Lab Medicine & Pathology, University of Minnesota, Minneapolis, MN, United States.

出版信息

Front Neurosci. 2021 Sep 9;15:718464. doi: 10.3389/fnins.2021.718464. eCollection 2021.

DOI:10.3389/fnins.2021.718464
PMID:34566565
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8458657/
Abstract

Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated calcium channels. The KLHL1 knockout (KO) model displays altered calcium channel expression in various brain regions. We analyzed the electrical behavior of hypothalamic POMC (proopiomelanocortin) neurons and their response to leptin. Leptin's effects on POMC neurons include enhanced gene expression, activation of the ERK1/2 pathway and increased electrical excitability. The latter is initiated by activation of the Jak2-PI3K-PLC pathway, which activates TRPC1/5 (Transient Receptor Potential Cation) channels that in turn recruit T-type channel activity resulting in increased excitability. Here we report over-expression of Ca3.1 T-type channels in the hypothalamus of KLHL1 KO mice increased T-type current density and enhanced POMC neuron basal excitability, rendering them electrically unresponsive to leptin. Electrical sensitivity to leptin was restored by partial blockade of T-type channels. The overexpression of hypothalamic T-type channels in POMC neurons may partially contribute to the obese and abnormal feeding phenotypes observed in KLHL1 KO mice.

摘要

Kelch样蛋白1（KLHL1）是一种神经元肌动蛋白结合蛋白，可调节电压门控钙通道。KLHL1基因敲除（KO）模型在各个脑区显示出钙通道表达的改变。我们分析了下丘脑促阿黑皮素原（POMC）神经元的电行为及其对瘦素的反应。瘦素对POMC神经元的作用包括增强基因表达、激活ERK1/2信号通路以及增加电兴奋性。后者由Jak2-PI3K-PLC信号通路的激活引发，该通路激活瞬时受体电位阳离子通道1/5（TRPC1/5），进而募集T型通道活性，导致兴奋性增加。在此我们报告，KLHL1基因敲除小鼠下丘脑中Ca3.1 T型通道的过表达增加了T型电流密度并增强了POMC神经元的基础兴奋性，使其对瘦素无电反应。通过部分阻断T型通道可恢复对瘦素的电敏感性。POMC神经元中下丘脑T型通道的过表达可能部分导致了在KLHL1基因敲除小鼠中观察到的肥胖和异常摄食表型。

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Involvement of calcium channels in the regulation of adipogenesis.
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