RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses


  • M.K. Grauel
  • M. Maglione
  • S. Reddy-Alla
  • C.G. Willmes
  • M.M. Brockmann
  • T. Trimbuch
  • T. Rosenmund
  • M. Pangalos
  • G. Vardar
  • A. Stumpf
  • A.M. Walter
  • B.R. Rost
  • B.J. Eickholt
  • V. Haucke
  • D. Schmitz
  • S.J. Sigrist
  • C. Rosenmund


  • Proceedings of the National Academy of Sciences of the United States of America


  • Proc Natl Acad Sci U S A 113 (41): 11615-11620


  • The tight spatial coupling of synaptic vesicles and voltage-gated Ca(2+) channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca(2+) channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca(2+) nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.