Presynaptic group III metabotropic glutamate receptors (mGluRs) and Ca2+ channels are the main neuronal activity-dependent regulators of synaptic vesicle release, and they use common molecules in their signaling cascades. Among these, calmodulin (CaM) and the related EF-hand Ca2+-binding proteins are of particular importance as sensors of presynaptic Ca2+, and a multiple of them are indeed utilized in the signaling of Ca2+ channels. However, despite its conserved structure, CaM is the only known EF-hand Ca2+-binding protein for signaling by presynaptic group III mGluRs. Because the mGluRs and Ca2+ channels reciprocally regulate each other and functionally converge on the regulation of synaptic vesicle release, the mGluRs would be expected to utilize more EF-hand Ca2+-binding proteins in their signaling. Here I show that calcium-binding protein 1 (CaBP1) bound to presynaptic group III mGluRs competitively with CaM in a Ca2+-dependent manner and that this binding was blocked by protein kinase C (PKC)-mediated phosphorylation of these receptors. As previously shown for CaM, these results indicate the importance of CaBP1 in signal cross talk at presynaptic group III mGluRs, which includes many molecules such as cAMP, Ca2+, PKC, G protein, and Munc18-1. However, because the functional diversity of EF-hand calcium-binding proteins is extraordinary, as exemplified by the regulation of Ca2+ channels, CaBP1 would provide a distinct way by which presynaptic group III mGluRs fine-tune synaptic transmission. (C) 2011 Elsevier Inc. All rights reserved.