2. Academic Validation
  3. RIM C2B Domains Target Presynaptic Active Zone Functions to PIP2-Containing Membranes

RIM C2B Domains Target Presynaptic Active Zone Functions to PIP2-Containing Membranes

  • Neuron. 2018 Apr 18;98(2):335-349.e7. doi: 10.1016/j.neuron.2018.03.011.
Arthur P H de Jong 1,  Carlos M Roggero 2,  Meng-Ru Ho 3,  Man Yan Wong 1,  Chad A Brautigam 4,  Josep Rizo 2,  Pascal S Kaeser 5
Affiliations

Affiliations

  • 1 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Departments of Biophysics, Biochemistry, and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Departments of Biophysics, Biochemistry, and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 4 Departments of Biophysics and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 29606581 DOI: 10.1016/j.neuron.2018.03.011
Abstract

Rapid and efficient synaptic vesicle fusion requires a pool of primed vesicles, the nearby tethering of CA2+ channels, and the presence of the phospholipid PIP2 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 PIP2 content. Here we find that the C2B domain of the active zone scaffold RIM is critical for action potential-triggered fusion. Remarkably, the known RIM functions in vesicle priming and CA2+ influx do not require RIM C2B domains. Instead, biophysical experiments reveal that RIM C2 domains, which lack CA2+ binding, specifically bind to PIP2. Mutational analyses establish that PIP2 binding to RIM C2B and its tethering to the Other RIM domains are crucial for efficient exocytosis. We propose that RIM C2B domains are constitutive PIP2-binding modules that couple mechanisms for vesicle priming and CA2+ channel tethering to PIP2-containing target membranes.

Keywords

C2 domain; PIP(2); RIM; active zone; neurotransmitter release; secretion; synaptic vesicle.

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