Ca2+ can inhibit or activate Ca2+ channels,

mediated by several EF-hand Ca2+-binding proteins. Specifically, calmodulin appears to both facilitate and inhibit voltage-dependent activation of Cav2.1 P/Q-type Ca2+ channels via binding to discrete sites in the cytoplasmic Ca2+ channel tail sequences (DeMaria et al., 2001 and Lee et al., 2003). In addition, another EF-hand Ca2+-binding protein called check details “calcium-binding protein 1” (CaBP1) increases inactivation of P/Q-type Ca2+ channels (Lee et al., 2002), whereas a third EF-hand Ca2+-binding protein called visinin-like protein 2 (VILIP-2) slows the rate of Ca2+ channel inactivation and enhances facilitation (Lautermilch et al., 2005). Moreover, Ca2+ channels are powerfully inhibited by G protein mediated mechanisms activated by presynaptic receptors, and such inhibition can also contribute to short-term synaptic plasticity. RG7204 order For example, GABAB-autoreceptors mediate short-term synaptic depression of inhibitory synapses during stimulus trains in insular cortex, illustrating this mode of short-term

synaptic plasticity (Kobayashi et al., 2012). However, most G protein mediated presynaptic inhibition of release by suppression of Ca2+ channel activation probably does not operate via autoreceptors, but via receptors for neuromodulators such as neuropeptides, endocannabinoids, acetylcholine, and catecholamines. The most prominent example of this process is depolarization-induced suppression of inhibition, a form of short-term plasticity where postsynaptically released endocannabinoids suppress presynaptic release of GABA by inhibiting presynaptic Ca2+ channels (Wilson and Nicoll, 2001). This widespread mechanism also operates outside of short-term plasticity to modulate entire neuronal ensembles, as seen for example in the

suppression of excitatory synaptic transmission at Schaffer collateral synapses in the CA1 region of the hippocampus by presynaptic Heterotrimeric G protein muscarinic receptors (Vogt and Regehr, 2001). In addition to short-term synaptic plasticity due to the interplay of residual Ca2+ and vesicle depletion and to the modulation of presynaptic Ca2+ channels, a third class of mechanisms mediates short-term plasticity via direct changes in the release machinery. Mutations in several proteins associated with the release machinery alter short-term plasticity in a manner independent of the first two sets of mechanisms, for example mutations in synapsins (Rosahl et al., 1995), Munc13 (Augustin et al., 1999), and RIMs (Schoch et al., 2002). The mechanisms by which these mutations cause such changes are largely unclear, except for one protein: Munc13. As we discussed earlier, Munc13 is an active zone protein that is essential for synaptic vesicle priming, probably because it catalyzes SNARE-complex formation via its MUN domain, and that is directly regulated by RIM proteins.