@article{303404bcbf40447e9f9e4fecb9fe247b,
title = " RIM C 2 B Domains Target Presynaptic Active Zone Functions to PIP 2 -Containing Membranes ",
abstract = " Rapid and efficient synaptic vesicle fusion requires a pool of primed vesicles, the nearby tethering of Ca 2+ channels, and the presence of the phospholipid PIP 2 in the target membrane. Although the presynaptic active zone mediates the first two requirements, it is unclear how fusion is targeted to membranes with high PIP 2 content. Here we find that the C 2 B domain of the active zone scaffold RIM is critical for action potential-triggered fusion. Remarkably, the known RIM functions in vesicle priming and Ca 2+ influx do not require RIM C 2 B domains. Instead, biophysical experiments reveal that RIM C 2 domains, which lack Ca 2+ binding, specifically bind to PIP 2 . Mutational analyses establish that PIP 2 binding to RIM C 2 B and its tethering to the other RIM domains are crucial for efficient exocytosis. We propose that RIM C 2 B domains are constitutive PIP 2 -binding modules that couple mechanisms for vesicle priming and Ca 2+ channel tethering to PIP 2 -containing target membranes. de Jong et al. demonstrate that the RIM C 2 B domain is important for neurotransmitter release. RIM C 2 B binds to the phospholipid PIP 2 , and this interaction directs synaptic vesicle priming and Ca 2+ influx to the PIP 2 -containing plasma membrane for efficient exocytosis. ",
keywords = "C2 domain, PIP, RIM, active zone, neurotransmitter release, secretion, synaptic vesicle",
author = "{de Jong}, {Arthur P.H.} and Roggero, {Carlos M.} and Ho, {Meng Ru} and Wong, {Man Yan} and Brautigam, {Chad A} and Jose Rizo-Rey and Kaeser, {Pascal S.}",
note = "Funding Information: We thank Lydia Bickford and Jennifer Jiexin Wang for technical support, Hajnalka Nyitrai for help with antibody production, Dr. Thomas S{\"u}dhof for antibodies, and Dr. Jonathan Cohen and members of the Kaeser laboratory for comments on the manuscript. This work was supported by grants from the NIH ( R01NS083898 and R01MH113349 to P.S.K. and R35NS097333 to J.R.), the Lefler Foundation (to A.d.J.), the NWO (Rubicon Fellowship 825.12.028 to A.d.J.), the Harvard Brain Initiative (to P.S.K.), and the Welch Foundation ( I-1304 to J.R.). The Agilent DD2 consoles of the 800 MHz spectrometer and one of the 600 MHz spectrometers used for the research presented here were purchased with shared instrumentation grants from the NIH ( S10OD018027 to J.R. and S10RR026461 to Michael K. Rosen). We also acknowledge the Neurobiology Imaging Facility (supported by the Core Center grant P30NS072030 ) and the Harvard Neurodiscovery Imaging Center. Funding Information: We thank Lydia Bickford and Jennifer Jiexin Wang for technical support, Hajnalka Nyitrai for help with antibody production, Dr. Thomas S?dhof for antibodies, and Dr. Jonathan Cohen and members of the Kaeser laboratory for comments on the manuscript. This work was supported by grants from the NIH (R01NS083898 and R01MH113349 to P.S.K. and R35NS097333 to J.R.), the Lefler Foundation (to A.d.J.), the NWO (Rubicon Fellowship 825.12.028 to A.d.J.), the Harvard Brain Initiative (to P.S.K.), and the Welch Foundation (I-1304 to J.R.). The Agilent DD2 consoles of the 800 MHz spectrometer and one of the 600 MHz spectrometers used for the research presented here were purchased with shared instrumentation grants from the NIH (S10OD018027 to J.R. and S10RR026461 to Michael K. Rosen). We also acknowledge the Neurobiology Imaging Facility (supported by the Core Center grant P30NS072030) and the Harvard Neurodiscovery Imaging Center.",
year = "2018",
month = apr,
day = "18",
doi = "10.1016/j.neuron.2018.03.011",
language = "English (US)",
volume = "98",
pages = "335--349.e7",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}