RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction.
At a synapse, fast synchronous neurotransmitter release requires localization of Ca(2+) channels to presynaptic active zones. How Ca(2+) 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 Ca(2+) channels but not L-type Ca(2+) 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 Ca(2+) channels. Strikingly, rescue of the decreased Ca(2+)-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 Ca(2+) channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse.
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305-5453, USA.
Pascal S
PS
Kaeser
Lunbin
L
Deng
Yun
Y
Wang
Irina
I
Dulubova
Xinran
X
Liu
Josep
J
Rizo
Thomas C
TC
Südhof
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques
D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D019204:GTP-Binding Proteins; D002118:Calcium
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