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A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release.
Proc Natl Acad Sci U S A
January 2025
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Neurotransmitter release is triggered in microseconds by Ca-binding to the Synaptotagmin-1 C-domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 CB domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca-binding loops away from the fusion site, hindering these putative activities.
View Article and Find Full Text PDFMinimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release.
Nat Commun
December 2024
Nanobiology Institute, Yale University, West Haven, CT, USA.
Neurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically relevant conditions to delineate the minimal protein machinery sufficient to account for various modes of calcium-triggered vesicle fusion dynamics.
View Article and Find Full Text PDFComprehensive study of SNAREs involved in the post-Golgi transport in photoreceptors.
Front Cell Dev Biol
December 2024
Program of Life and Environmental Science, Graduate School of Integral Science for Life, Hiroshima University, Hiroshima, Japan.
Polarized transport is essential for the construction of multiple plasma membrane domains within cells. photoreceptors serve as excellent model systems for studying the mechanisms of polarized transport. We conducted a comprehensive soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) screening of the fly genome using RNAi knockdown and CRISPR/Cas9 somatic knockout combined with the CoinFLP system to identify SNAREs involved in post-Golgi trafficking.
View Article and Find Full Text PDFVesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1.
Biophys J
December 2024
Cellular and Molecular Physiology, School of Medicine, Yale University, New Haven, CT; Nanobiology Institute, Yale University, West Haven, CT; Molecular Biophysics and Biochemistry, Yale University, New Haven, CT; Saints-Pères Paris Institute for the Neurosciences (SPPIN), Université de Paris, Centre National de la Recherche Scientifique (CNRS) UMR 8003, Paris, France; Wu Tsai Institute, Yale University. Electronic address:
Synaptotagmin-1 (Syt1) is a major calcium sensor for rapid neurotransmitter release in neurons and hormone release in many neuroendocrine cells. It possesses two tandem cytosolic C2 domains that bind calcium, negatively charged phospholipids, and the neuronal SNARE complex. Calcium binding to Syt1 triggers exocytosis, but how this occurs is not well understood.
View Article and Find Full Text PDFThe role of CAPS in Ca-regulated exocytosis: Promotion of vesicle tethering, priming, and fusion.
Neuropharmacology
March 2025
Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. Electronic address:
Neurotransmitter and neuromodulator release by Ca-regulated exocytosis is essential for information transmisson between cells. Formation of SNARE complex (soluble N-ethylmaleimide sensitive factor attachment protein receptors) provide energy to bring vesicles and the plasma membranes together and catalyze membrane fusion. The "Ca-dependent activator protein for secretion" (CAPS) assumes a pivotal role in facilitating vesicle content release, not only in the nervous system but also in various other secretory tissues.
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