Metabotropic Glutamate Receptors and Interacting Proteins in Epileptogenesis

Abstract

Neurotransmitter and receptor systems are involved in different neurological and neuropsychological disorders such as Parkinson's disease, depression, Alzheimer's disease and epilepsy. Recent advances in studies of signal transduction pathways or interacting proteins of neurotransmitter receptor systems suggest that different receptor systems may share the common signal transduction pathways or interacting proteins which may be better therapeutic targets for development of drugs to effectively control brain diseases. In this paper, we reviewed metabotropic glutamate receptors (mGluRs) and their related signal transduction pathways or interacting proteins in status epilepticus and temporal lobe epilepsy, and proposed some novel therapeutical drug targets for controlling epilepsy and epileptogenesis.

Fig. (1)

Interactions among mGluRs and the interacting proteins in the pre- and post-synaptic membrane and subsequent epileptogenesis. Glutamate released from the pre-synaptic membrane bind and open ligand-gated ionotropic glutamate receptors (iGluRs) allowing Na⁺ and/or Ca²⁺ influx and/or K⁺ efflux at the central area of postsynaptic membrane. Over release of glutamate activates metabotropic glutamate receptors (mGluRs) at the peripheral of post-synaptic membrane, induces the following cascades of reactions: 1) the formation of signaling complexes by dimerization of the long form Homers which then enhances the activity of iGluRs; 2) phospholipase C (PLC) cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP₂) leading to an increase in diacylglycerol (DAG) and inositol triphosphate (IP₃); 3) IP3 activates IP₃ receptors which induces Ca²⁺ efflux from endoplasmic reticulum (ER); 4) Protein kinase C (PKC) activation by the increased concentration of Ca²⁺ and DAG; 5) PKC phosphorylation of the S901 of mGluR5 to reduce its postsynaptic membrane expressing level; 6) calmodulin (CaM) binding which prevents phosphorylation of the mGluRs by PKC in a Ca²⁺-dependent manner, while the Seven in absentia homolog (Siah)-1 and norbin compete with CaM to enhance the possibility of PKC phosphorylation; 7) dissociation of CaM and released Ca²⁺ open K⁺ channels on postsynaptic membrane to induce a neuroprotective hyperpolarization; 8-9) phosphorylation of NMDAR by the activated CaMKII and then opening of the NMDAR-dependent Ca²⁺ channel; 10) binding of glutamate with presynaptic mGluR7 to enhance the possibility of PKC phosphorylation with the help of the protein interacting with C kinase 1 (PICK1) which compete with CaM; 11) PKC phosphorylation of the S901 of mGluR7 to down-regulate the release of presynaptic neurotransmitters; 12) uptaking glutamate back to presynaptic nerve ending by excitatory amino-acid transporters (EAAT) to reduce excitatory response on postsynaptic membrane; 13-14) up-regulation of endocannabinoid (eCB) and activation of mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) by PKC phosphorylation; 15) fine-tuning PKC activities may induce synergic action of various neurotransmitters and receptors system, for instance, 16) PKC inhibition induces GABA_A receptor hypersensitivity, reduces mGluR5 related epileptiform bursts, and therefore, PKC may be an ideal therapeutic target to prevent epileptogenesis.