Presynaptic neurons self- tune by inversely coupling neurotransmitter release with the abundance of CaV2 voltage- gated Ca2+channels

• 成果类型: Article
• 署名作者: Xiong, Ame; Richmond, Janet E.; Kim, Hongkyun
• 署名单位: Chicago Medical School; Rosalind Franklin University of Medicine & Science; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13673
• DOI: 10.1073/pnas.2404969121
• 发表日期: 2024-08-27
• 关键词: synaptic vesicle docking; caenorhabditis-elegans; retrograde signal; calcium-channels; ca2+ channels; active zones; plasticity; protein; endophilin; syntaxin

摘要

The abundance of CaV2 voltage- gated calcium channels is linked to presynaptic homeostatic plasticity (PHP), a process that recalibrates synaptic strength to maintain the stability of neural circuits. However, the molecular and cellular mechanisms governing PHP and CaV2 channels are not completely understood. Here, we uncover a previously not described form of PHP in Caenorhabditis elegans, revealing an inverse regulatory relationship between the efficiency of neurotransmitter release and the abundance of UNC-2/CaV2 channels. Gain- of- function unc- 2SL(S240L) mutants, which carry a mutation analogous to the one causing familial hemiplegic migraine type 1 in humans, showed markedly reduced channel abundance despite increased channel functionality. Reducing synaptic release in these unc- 2SL(S240L) mutants restored channel levels to those observed in wild- type animals. Conversely, loss- of- function unc- 2DA(D726A) mutants, which harbor the D726A mutation in the channel pore, exhibited a marked increase in channel abundance. Enhancing synaptic release in unc-2DA mutants reversed this increase in channel levels. Importantly, this homeostatic regulation of UNC-2 channel levels is accompanied by the structural remodeling of the active zone (AZ); specifically, unc-2DA mutants, which exhibit increased channel abundance, showed parallel increases in select AZ proteins. Finally, our forward genetic screen revealed that WWP-1, a HECT family E3 ubiquitin ligase, is a key homeostatic mediator that removes UNC-2 from synapses. These findings highlight a self- tuning PHP regulating UNC-2/CaV2 channel abundance along with AZ reorganization, ensuring synaptic strength and stability.