RIM Proteins Activate Vesicle Priming by Reversing Autoinhibitory Homodimerization of Munc13.
Journal - Neuron
At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that-among others-mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn(2+) finger domain of RIMs binds to the C(2)A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it. Here, we show that RIMs mediate vesicle priming not by coupling Munc13 to other active zone proteins as thought but by directly activating Munc13. Specifically, we found that the isolated Zn(2+) finger domain of RIMs autonomously promoted vesicle priming by binding to Munc13, thereby relieving Munc13 homodimerization. Strikingly, constitutively monomeric mutants of Munc13 rescued priming in RIM-deficient synapses, whereas wild-type Munc13 did not. Both mutant and wild-type Munc13, however, rescued priming in Munc13-deficient synapses. Thus, homodimerization of Munc13 inhibits its priming function, and RIMs activate priming by disrupting Munc13 homodimerization.Copyright Â© 2011 Elsevier Inc. All rights reserved.
RIM1 and RIM1ß Are Synthesized from Distinct Promoters of the RIM1 Gene to Mediate Differential But Overlapping Synaptic Functions
Journal - Journal of Neuroscience
At a synapse, presynaptic terminals form a specialized areaof the plasma membrane called the active zone that mediatesneurotransmitter release. RIM1 is a multidomain protein thatconstitutes a central component of the active zone by bindingto other active zone proteins such as Munc13 s, -liprins, andELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1.In mice, knockout of RIM1 significantly impairs synaptic vesiclepriming and presynaptic long-term plasticity, but is not lethal.We now find that the RIM1 gene encodes a second, previouslyunknown RIM1 isoform called RIM1ß that is upregulated inRIM1 knock-out mice. RIM1ß is identical to RIM1 exceptfor the N terminus where RIM1ß lacks the N-terminal Rab3-bindingsequence of RIM1. Using newly generated knock-out mice lackingboth RIM1 and RIM1ß, we demonstrate that different fromthe deletion of only RIM1, deletion of both RIM1 and RIM1ßseverely impairs mouse survival. Electrophysiological analysesshow that the RIM1ß deletion abolishes long-term presynapticplasticity, as does RIM1 deletion alone. In contrast, the impairmentin synaptic strength and short-term synaptic plasticity thatis caused by the RIM1 deletion is aggravated by the deletionof both RIM1 and RIM1ß. Thus, our data indicate that theRIM1 gene encodes two different isoforms that perform overlappingbut distinct functions in neurotransmitter release.
|Keywords : ||RIM • Rab3 • Munc13 • active zone • synaptic plasticity • neurotransmitter release|