Journal article
An ArfGAP-dependent signaling modulates synaptic plasticity via IP3-regulated calcium release from the endoplasmic reticulum
PLoS genetics, Vol.22(1), e1012031
01/23/2026
DOI: 10.1371/journal.pgen.1012031
PMID: 41576032
Abstract
Calcium release from intracellular stores influences synaptic response timing and magnitude. Despite the critical role of inositol trisphosphate (IP3)- and ryanodine receptor (RyR)-dependent calcium release in regulating synaptic strength, the upstream signaling mechanisms that govern IP3 receptor or RyR activity remain elusive. Here, we provide evidence that the ArfGAP-containing protein Asap modulates NMJ morphogenesis and synaptic calcium homeostasis by activating IP3-mediated calcium release from the endoplasmic reticulum (ER) via the phospholipase C-beta (PLCβ) signaling pathway. Using CRISPR/Cas9-engineered Asap mutants and genetically encoded calcium sensors, we demonstrate that loss of Asap leads to elevated resting synaptic calcium, resulting in increased evoked amplitude, elevated spontaneous miniature frequency, and reduced synaptic failures under low extracellular calcium conditions. Additional pharmacological and genetic manipulations of calcium regulatory pathways further support the role of increased resting intracellular calcium in driving enhanced neurotransmission in Asap-deficient synapses. Consistent with the role of Asap's ArfGAP domain in NMJ morphogenesis and intracellular calcium regulation, expressing a GDP-locked form of Arf6 (Arf6DN) or knocking down Arf6 in Asap mutants not only rescues Asap-associated synaptic defects but also normalizes synaptic calcium levels. Furthermore, epistatic analysis revealed that attenuation of IP3-signaling components in animals constitutively expressing Arf6CA normalized the NMJ morphological defects and synaptic functions. Together, these findings provide novel insights into the role of Asap-Arf6-PLCβ signaling in IP3-regulated calcium dynamics, sustaining both structural and functional synaptic plasticity.
Details
- Title: Subtitle
- An ArfGAP-dependent signaling modulates synaptic plasticity via IP3-regulated calcium release from the endoplasmic reticulum
- Creators
- Bhagaban Mallik - University of IowaShikha Kushwaha - Indian Institute of Science Education and Research, BhopalAnjali Bisht - Indian Institute of Science Education and Research, BhopalHarsha Mj - Indian Institute of Science Education and Research, BhopalC Andrew Frank - University of IowaVimlesh Kumar - Indian Institute of Science Education and Research, Bhopal
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.22(1), e1012031
- DOI
- 10.1371/journal.pgen.1012031
- PMID
- 41576032
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7404
- eISSN
- 1553-7404
- Language
- English
- Date published
- 01/23/2026
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9985130241102771
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