Caenorhabditis elegans junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin.

IF 3.3 3区生物学

Genetics Pub Date : 2021-08-09 DOI:10.1093/genetics/iyab063

Christopher A Piggott, Zilu Wu, Stephen Nurrish, Suhong Xu, Joshua M Kaplan, Andrew D Chisholm, Yishi Jin

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引用次数: 0

Abstract

The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole Caenorhabditis elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 colocalizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68 RyR calcium channel, and is required for animal movement. In neurons, JPH-1 colocalizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in the soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell nonautonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and with unc-68 for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68 is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

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秀丽隐杆线虫嗜结膜蛋白具有组织特异性功能，并通过突触延伸蛋白调节神经传递。

嗜junctophilin蛋白家族将质膜（PM）和内质网（ER）膜连接在一起，并耦合PM和ER定位的钙通道。了解嗜junctophilins的体内功能对于解剖ER-PM接触位点的生理作用具有重要意义。在这里，我们发现唯一的秀丽隐杆线虫嗜junctophilin JPH-1定位于神经元和肌肉中的离散膜接触位点，并具有重要的组织特异性功能。jph-1无效突变体由于咽肌收缩较弱，导致进食减少，生长发育缓慢。在体壁肌肉中，JPH-1与PM定位的EGL-19电压门控钙通道和ER定位的UNC-68 RyR钙通道共定位，是动物运动所必需的。在神经元中，JPH-1与胞体中的膜接触位点蛋白Extended SYnaptoTagmin 2（ESYT-2）共定位，并存在于突触前释放位点附近。有趣的是，jph-1和esyt-2无效突变体在对涕灭威的反应中表现出相互抑制，这表明jph-1和esyt-2在神经肌肉突触传递中具有拮抗作用。此外，我们发现jph-1在损伤后轴突再生中具有意想不到的细胞非自主作用。遗传双突变体分析表明，jph-1与两个PM定位的电压门控钙通道egl-19和unc-2以及unc-68在动物健康和发育方面的作用途径重叠。最后，我们发现jph-1调节EGL-19和UNC-68的共定位，并且UNC-68是jph-1定位到ER-PM点所必需的。我们的数据证明了亲junctophilin在细胞生理学中的重要作用，也为亲Junctolhilin如何与体内其他钙通道一起发挥作用提供了见解。

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来源期刊

Genetics 生物-遗传学

CiteScore

6.20

自引率

6.10%

发文量

177

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