TY - JOUR
T1 - RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction
AU - Kaeser, Pascal S.
AU - Deng, Lunbin
AU - Wang, Yun
AU - Dulubova, Irina
AU - Liu, Xinran
AU - Rizo-Rey, Jose
AU - Südhof, Thomas C.
N1 - Funding Information:
We thank E. Borowicz, I. Kornblum, L. Fan, J. Mitchell, H. Ly, and I. Huryeva for technical assistance, Dr. R.E. Hammer for blastocyst injections, Dr. N. Brose for Munc13-1 antibodies, Dr. C. Acuna-Goycolea for advice on Ca 2+ -imaging experiments, Dr. Z. Ma for assistance with yeast two-hybrid screening, Drs. Z. Pang, T. Bacaj, and C. Földy for help with data analysis, and Dr. R. Schneggenburger for comments. This work was supported by grants from the NIH (NINDS 33564 to T.C.S., NS37200 to J.R., DA029044 to P.S.K.), a Swiss National Science Foundation Postdoctoral Fellowship (to P.S.K.), and a NARSAD Young Investigator Award (to P.S.K.).
PY - 2011/1/21
Y1 - 2011/1/21
N2 - At a synapse, fast synchronous neurotransmitter release requires localization of Ca2+ channels to presynaptic active zones. How Ca2+ channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca2+ channels but not L-type Ca2+ channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca2+ channels. Strikingly, rescue of the decreased Ca2+-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca2+ channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse.
AB - At a synapse, fast synchronous neurotransmitter release requires localization of Ca2+ channels to presynaptic active zones. How Ca2+ channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca2+ channels but not L-type Ca2+ channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca2+ channels. Strikingly, rescue of the decreased Ca2+-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca2+ channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse.
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U2 - 10.1016/j.cell.2010.12.029
DO - 10.1016/j.cell.2010.12.029
M3 - Article
C2 - 21241895
AN - SCOPUS:78651509693
SN - 0092-8674
VL - 144
SP - 282
EP - 295
JO - Cell
JF - Cell
IS - 2
ER -