RIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone

Abstract

Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1alpha, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and alpha-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1alpha in mice shows that RIM1alpha is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1alpha has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.

Molecular architecture of glycinergic synapses

“…However, genetic deletion of such pan-synaptic scaVolding proteins often has diVerent eVects on excitatory than on inhibitory presynaptic terminals. This holds true, e.g., for Munc13s (Schoch et al 2002;Varoqueaux et al 2002), RIM1 (Schoch et al 2002), and CASK ). Likewise, triple knockout of the synaptic vesicle associated cytomatrix proteins Synapsin 1, 2 and 3 changes the kinetics of synaptic depression, but not basal transmission, at excitatory synapses, whereas the kinetics of depression are unchanged, but basal transmission is reduced, at inhibitory synapses (Gitler et al 2004).…”

Active zones for presynaptic plasticity in the brain

“…RIM1-alpha, the best studied isoform, is located at the active zone of the presynaptic terminals and forms a protein scaffold interacting with key presynaptic molecules. In addition to Rab3a, RIM1-alpha binds active zone proteins Munc13-1 147,148 and ERCs, 149,150 the synaptic vesicle protein synaptotagmin1, a calcium sensor for fast synchronous release, 151,152 and other synaptic proteins as alpha-liprins. 152 Indirectly, RIM1-alpha binds to L-type calcium channels 153 through the so-called RIM-BPs (RIM binding proteins).…”

“…In addition to Rab3a, RIM1-alpha binds active zone proteins Munc13-1 147,148 and ERCs, 149,150 the synaptic vesicle protein synaptotagmin1, a calcium sensor for fast synchronous release, 151,152 and other synaptic proteins as alpha-liprins. 152 Indirectly, RIM1-alpha binds to L-type calcium channels 153 through the so-called RIM-BPs (RIM binding proteins). 150 Insightful functional studies of RIM have been recently performed in C. elegans 154 and in knockout mice.…”

“…150 Insightful functional studies of RIM have been recently performed in C. elegans 154 and in knockout mice. 152,155,156,126 Schoch et al 152 have shown that mice lacking RIM1-alpha survived to adulthood with slighter high mortality compared to wild-type littermates and displayed a poor maternal and nurturing behavior. They did not show any structural abnormalities in the brain and did not have significant changes in the levels of synaptic proteins, except for the active zone protein Munc13-1 which was decreased by B60% probably because, since Munc-13 binds to RIM1-alpha, it degrades when RIM1-alpha is absent.…”

“…Since Munc13-1 is a key priming factor, 124,125,130 they concluded that the missing 50% of the RRP could be explained because in RIM1-alpha knockout mice, there is a substantial reduction in Munc13-1 levels. 152 That implies that there are probably two different subpools of synaptic vesicles within the RRP. The missing subpool of the RRP in RIM1-alpha KO mice probably corresponds in normal conditions to a pool of synaptic vesicles activated by a priming reaction where the interaction between Munc13-1 and RIM1-alpha is required.…”