Cdk5 PhosPhorylation of MunC18-1 EnhanCEs synaPtiC transMission
نویسندگان
چکیده
in preparation 96 4 Abstract Cyclin-dependent kinase 5 (Cdk5) functions in many neuronal processes and has recently been implicated in homeostatic plasticity. Cdk5 activation results in reallocation of synaptic strength, including weakening of some connections while strengthening others. The molecular mechanisms underlying these phenomena are thus far not understood. We show that Cdk5 phosphorylation of the presynaptic protein Munc18-1 plays an important role in the regulation of synaptic strength. In the absence of phosphorylation, neurons show reduced spontaneous and evoked release, RRP size and release probability. Hence, Cdk5 phosphorylation of Munc18-1 does not underlie Cdk5-dependent silencing of synapses, but may play a role in neuronal silencing induced increase of presynaptic strength.
منابع مشابه
Cyclin-dependent kinase 5 phosphorylation of human septin SEPT5 (hCDCrel-1) modulates exocytosis.
Cyclin-dependent kinase 5 (Cdk5) is predominantly expressed in the nervous system, where it is involved in neuronal migration, synaptic transmission, and survival. The role of Cdk5 in synaptic transmission is mediated by regulating the cellular functions of presynaptic proteins such as synapsin, Munc18, and dynamin 1. Its multifunctional role at the synapse is complex and probably involves othe...
متن کاملCdk5 stimulates secretion via munc18-1 Cyclin-dependent Kinase 5 Associated with p39 Promotes Munc18-1 Phosphorylation and Ca-dependent Exocytosis
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine protein kinase that requires association with a regulatory protein, p35 or p39, to form an active enzyme. Munc18-1 plays an essential role in membrane fusion and its function is regulated by phosphorylation. We report here that both p35 and p39 are expressed in insulin-secreting ß-cells, where they exhibited individual subc...
متن کاملAlternative splicing of Munc18-1 regulates short-term synaptic depression
Themunc18-1 gene encodes two splice-variants for the far C-terminus of the protein, which are expressed at different levels in different regions of the adult mammalian brain. Here, we investigate whether these splice variants are functionally different. Synaptic transmission was tested in hippocampal neurons depending solely on Munc18-1a or Munc18-1b for synaptic vesicle release. We show that a...
متن کاملTyrosine phosphorylation of Munc18-1 determines synaptic strength
Tyrosine kinases are important regulators of synaptic strength. Here we identify Munc181, an essential component of synaptic vesicle release machinery, as a target for neuronal tyrosine kinase n-Src. Disrupting the main Src phosphorylation site on Munc18-1 leads to severe defects in spontaneous and evoked synaptic transmission in autaptic hippocampal neurons, which can be temporarily restored b...
متن کاملPresynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.
Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediates CB1R- and mGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuro...
متن کامل