Selective optogenetic inhibition of Gαq or Gαi signaling by minimal RGS domains disrupts circuit functionality and circuit formation

• 成果类型: Article
• 署名作者: Lockyer, Jayde L.; Reading, Andrew; Vicenzi, Silvia; Zbela, Agnieszka; Viswanathan, Saranya; Delandre, Caroline; Newland, Jake W.; McMullen, John P. D.; Marshall, Owen J.; Gasperini, Robert; Foa, Lisa; Lin, John Y.
• 署名单位: University of Tasmania; University of Tasmania; Menzies Institute for Medical Research; University of Tasmania; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12793
• DOI: 10.1073/pnas.2411846121
• 发表日期: 2024-09-03
• 关键词: g-protein selectivity; adenylyl-cyclase; receptor; regulator; activation; expression; octopamine; mutations; courtship; g(q)alpha

摘要

Optogenetic techniques provide genetically targeted, spatially and temporally precise approaches to correlate cellular activities and physiological outcomes. In the nervous system, G protein- coupled receptors (GPCRs) have essential neuromodulatory functions through binding extracellular ligands to induce intracellular signaling cascades. In this work, we develop and validate an optogenetic tool that disrupts G alpha q signaling through membrane recruitment of a minimal regulator of G protein signaling (RGS) domain. This approach, Photo- induced G alpha Modulator-Inhibition of G alpha q (PiGM-Iq), exhibited potent and selective inhibition of G alpha q signaling. Using PiGM-Iq we alter the behavior of Caenorhabditis elegans and Drosophila with outcomes consistent with GPCR-G alpha q disruption. PiGM-Iq changes axon guidance in cultured dorsal root ganglia neurons in response to serotonin. PiGM-Iq activation leads to developmental deficits in zebrafish embryos and larvae resulting in altered neuronal wiring and behavior. Furthermore, by altering the minimal RGS domain, we show that this approach is amenable to G alpha i signaling. Our unique and robust optogenetic G alpha inhibiting approaches complement existing neurobiological tools and can be used to investigate the functional effects neuromodulators that signal through GPCR and trimeric G proteins.