Kainate Receptor Activation Induces Glycine Receptor Endocytosis Through PKC DeSUMOylation

Proper neuronal excitability is essential to neuronal function and is fine tuned by a balance between receptor-mediated synaptic excitation and inhibiton. In spinal cord, glycine receptor(GlyR), glycine-gated chloride channel, primarily mediates inhibitory neuronal transmission. Kainate receptor(KAR), a subtype of ionotropic glutamate receptors, mediates excitatory neuronal transmission. Surface expression of glycine receptor plays an important role in balancing neuronal output. There are several ways to regulate endocytosis, exocytosis, recycling and degradation to maintain proper surface expression of GlyR. In addition, lateral movement from and to the postsynaptic loci regulate postsynaptic stabilization of GlyR. SUMOylation(SUMO modification) is of critical importance for maintaining neuronal function in the central nervous system(CNS). SUMOylation is readily and rapidly reversed by sentrin-specific protease(SENP). The balance between SUMOylation / deSUMOylation of a specific protein stays in a highly reversible cycle regulating proteins location, activity, function and so on. To unravel the roles of SUMOylation in CNS, mechanisms that regulate SUMOylation / deSUMOylation are of particular interest.Taking advantage of immunocytochemistry, biochemistry, electrophysiology, etc., here we show, on cultured spinal cord neuron, activation of KAR by kainate induce calcium- and PKC-dependent GlyR internalization, leading to reduced inhibitory synaptic transmission. The crosstalk between KAR and GlyR relies on SENP1-mediated deSUMOylation of PKC. The status of PKC SUMOylation affects PKC activity: only when PKC are deSUMOylated through SENP1, can they be activated. SENP1 deficiency impairs PKC activation and GlyR endocytosis induced by kainate. SENP1-mediated deSUMOylation of PKC is essential for kainate-induced internalization of GlyR and thus plays a role in neuronal transsmion.We report here a novel anti-homeostatic regulation type of SENP1-mediated GlyR internalization that may participate in neuronal activity regulation. Activation of KARs which are excitatory ion channels, promotes inhibitory ion channel GlyR endocytosis.