Ca2+-dependent release of Munc18-1 from presynaptic mGluRs in short-term facilitation.
Short-term synaptic facilitation plays an important role in information processing in the central nervous system. Although the crucial requirement of presynaptic Ca(2+) in the expression of this plasticity has been known for decades, the molecular mechanisms underlying the plasticity remain controversial. Here, we show that presynaptic metabotropic glutamate receptors (mGluRs) bind and release Munc18-1 (also known as rbSec1/nSec1), an essential protein for synaptic transmission, in a Ca(2+)-dependent manner, whose actions decrease and increase synaptic vesicle release, respectively. We found that mGluR4 bound Munc18-1 with an EC(50) for Ca(2+) of 168 nM, close to the resting Ca(2+) concentration, and that the interaction was disrupted by Ca(2+)-activated calmodulin (CaM) at higher concentrations of Ca(2+). Consistently, the Munc18-1-interacting domain of mGluR4 suppressed both dense-core vesicle secretion from permeabilized PC12 cells and synaptic transmission in neuronal cells. Furthermore, this domain was sufficient to induce paired-pulse facilitation. Obviously, the role of mGluR4 in these processes was independent of its classical function of activation by glutamate. On the basis of these experimental data, we propose the following model: When neurons are not active, Munc18-1 is sequestered by mGluR4, and therefore the basal synaptic transmission is kept low. After the action potential, the increase in the Ca(2+) level activates CaM, which in turn liberates Munc18-1 from mGluR4, causing short-term synaptic facilitation. Our findings unite and provide a new insight into receptor signaling and vesicular transport, which are pivotal activities involved in a variety of cellular processes.
Nakajima
Yoshiaki
Y
Department of Biological Sciences, Faculty of Medicine, Kyoto University, Kyoto, Japan. yoshiaki@phy.med.kyoto-u.ac.jp
Mochida
Sumiko
S
Okawa
Katsuya
K
Nakanishi
Shigetada
S
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004964:Estriol / Q000031:analogs & derivatives* / Q000378:metabolism; D051379:Mice; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D009435:Synaptic Transmission
D051938:Munc18 Proteins; D018094:Receptors, Metabotropic Glutamate; C497938:Stxbp1 protein, mouse; C497939:Stxbp1 protein, rat; C009341:estriol succinate; D004964:Estriol; D002118:Calcium; C108823:metabotropic glutamate receptor 4