Similar to that in hippocampal synapses, several lines of evidence suggested that genetic elimination of RIMs interfered with the coupling between Ca2+ channels and transmitter release (Table 1). First, the presynaptic Ca2+ channel density was reduced. Because the gating properties of Ca2+ channels were unchanged, this suggests a reduction in the density of presynaptic Ca2+ channel proteins (see Kaeser et al., 2011). Second, the intrinsic Ca2+ sensitivity of transmitter release measured by Ca2+ uncaging was diminished. Third, the amplitude of the Ca2+ concentration transient at the Ca2+ sensor,

estimated from a comparison of synaptic data and uncaging data, was altered, again consistent selleck products with a loosening of the coupling between Ca2+ channels and Ca2+ sensors of exocytosis. The results (Kaeser et al., 2011 and Han et al., 2011) converge on the conclusion that RIMs change the coupling between Ca2+ channels and transmitter

release. However, the paper of Han et al. (2011), and in particular another extensive study by Deng et al. (2011), suggests that this is only one side of Alectinib mw the coin. At both the hippocampal synapses and the calyx of Held, the size of the releasable pool of synaptic vesicles is reduced in the RIM double knockout mouse. In the hippocampal synapses, pool size was measured by application of hypertonic sucrose solution (Deng et al., 2011). At the calyx of Held, the size of the readily releasable pool was elegantly probed in Ca2+ uncaging experiments (Han et al., 2011). Based on serial

electron microscopy analysis of calyx synapses, Han et al. suggest a reduction in the number of docked vesicles in RIM-deficient synapses. Thus, a docking deficit may underlie the reduction in pool size. In contrast, in the hippocampal synapses, genetic elimination of RIM appears to involve Munc13, a classical priming factor (Betz et al., 2001). This suggests that RIM regulates pool size via effects on priming. How do the different domains of RIM mediate these diverse functions? For the tethering function of RIM, rescue experiments suggest that both the PDZ domain and DNA ligase the proline-rich domain of RIM are necessary and sufficient for the effects (Kaeser et al., 2011). In contrast, the Rab3 binding domain seems to be dispensable. Because the proline-rich region of RIM represents the site of interaction with RIM-BPs (Hibino et al., 2002), the results suggest that a tripartite complex of RIMs, RIM-BPs, and Ca2+ channels is formed during tethering (Figure 1). For the priming function, the Zn2+ finger domain of RIM is necessary and sufficient (Deng et al., 2011). Because this site interacts with Munc13, this suggests that the effects on priming are mediated by Munc13 (Betz et al., 2001).