It is generally thought that RIMs operate as Rab3 effectors. Furthermore, RIMs are substrates of PKA and are thought to play important roles in presynaptic forms of synaptic plasticity

(Wang et al., 1997 and Castillo et al., 2002). Three recent papers (Kaeser et al., 2011, Han et al., 2011 and Deng et al., 2011; the latter two of which can be found in this issue of Neuron) shed new light on the function of RIMs, approaching the problem by genetic elimination (knockout). RIM proteins in mammals are highly diverse. They are encoded by four genes (Rim1–4) that drive the expression of seven known RIM isoforms: RIM1α and 1β; RIM2α, 2β, and VRT752271 nmr 2γ; RIM3γ; and RIM4γ. Unfortunately, RIM1α and RIM2α double knockout mice die immediately after birth ( Schoch et al., 2006), preventing a systematic analysis of the function of RIMs in synaptic transmission. The Südhof group ( Kaeser et al., 2011) has now solved this problem by generating a new mouse line in which both RIM1 and RIM2

genes are flanked by loxP sites (floxed). Because RIM3 and RIM4 are selectively expressed in short γ versions (composed of only a single C2 domain), this allows conditional elimination of all long forms of RIM. Kaeser et al. (2011) have addressed the function of RIMs in an elegant series of biochemical and electrophysiological experiments. The starting point of the analysis was the finding that RIMs directly and specifically interact with P/Q- and N-type Ca2+ channels. www.selleckchem.com/products/i-bet-762.html Kaeser et al. then systematically examined the functional significance of this molecular interaction, measuring synaptic currents in cultured hippocampal neurons. To eliminate RIMs from these synapses, lentiviral infection followed by Cre recombinase expression was used. Multiple pieces of evidence suggested that genetic elimination of RIMs changed the coupling between Ca2+ channels and transmitter release (Table 1). not First, the amplitude of evoked inhibitory postsynaptic currents (IPSCs) was reduced. Second, evoked release was desynchronized. Third, the onset of the blocking effects

of the Ca2+ chelator EGTA-AM was prolonged, suggesting a loosening of the coupling between Ca2+ channels and Ca2+ sensors of exocytosis (Neher, 1998 and Bucurenciu et al., 2008). Fourth, the dependence of release on the external Ca2+ concentration was shifted to higher concentrations. Finally, the amplitude of presynaptic Ca2+ concentration transients measured by fluorescent Ca2+ indicators was reduced. Taken together, these results suggest that conditional knockout of RIMs impairs the tethering of presynaptic Ca2+ channels to the active zone of inhibitory synapses. Han et al. (2011) have used the same mouse line to examine the function of RIMs at the calyx of Held, a glutamatergic synapse in the auditory brainstem accessible to quantitative biophysical analysis of transmitter release. To eliminate RIMs from these synapses, the new RIM1 and RIM2 floxed mouse line (Kaeser et al.