The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy
Abstract
:1. Introduction
2. Epilepsy Model and Antiepileptic Drugs
3. GABAergic Dysfunction in Epilepsy
4. Phospholipase C Beta (PLCβ) and GABAergic Inhibition
5. Phospholipase C Gamma (PLCγ) and GABAergic Inhibition
6. Concluding Remark and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
E/I balance | Excitation and inhibition balance |
PLC | Phospholipase C |
GABA | γ-aminobutyric acid |
GAD | Glutamic acid decarboxylase |
VGAT | Vesicular GABA transporter |
AED | Antiepileptic drug |
PIP2 | Phosphatidylinositol 4,5-bisphosphate |
IP3 | Inositol 1,4,5-triphosphate |
DAG | Diacylglycerol |
PKC | Protein kinase C |
GPCR | G protein-coupled receptor |
RTK | Receptor tyrosine kinase |
BDNF | Brain-derived neurotrophic factor |
TrkB | Tropomycin receptor kinase B |
AAV | Adeno-associated virus |
GAT | GABA transporter |
EPSC | Excitatory postsynaptic current |
IPSC | Inhibitory postsynaptic current |
KCC | K+-Cl– cotransporter |
nAChR | Nicotinic acetylcholine receptor |
mGluR | Metabotropic glutamate receptor |
EGF | Epidermal growth factor |
PDGF | Platelet-derived growth factor |
NGF | Nerve growth factor |
FGF | Fibroblast growth factor |
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Type | Epilepsy Model | Mechanism | Symptoms | Reference |
---|---|---|---|---|
Genetic | Genetic Absence Epilepsy Rat from Strasbourg (GAERS) | Inbred strain Mutation of Cacna1h gene encoding CaV3.2 T-type calcium channel | Spike-and-wave discharges (SWD) in EEG | [33,41] |
WAG/Rij | Polygenic gene mutation | Spike-and-wave discharges (SWD) in EEG | [42,43] | |
DBA/2 | Mutation of Asp2 gene | Audiogenic seizures | [34,35] | |
Genetically epilepsy-prone rats (GEPR) | GABAergic, serotonergic, noradrenergic deficits | Audiogenic, generalized tonic-clonic seizures | [33] | |
Electrical | Kindling | Lower threshold by repeated stimulation | Temporal lobe epilepsy | [30,31,32] |
Chemical | Pilocarpine | Muscarinic acetylcholine receptor agonist | Generalized tonic–clonic seizures | [24,25,26] |
Kainic acid | L-glutamate analog | Temporal lobe epilepsy | [27,28,29] |
Drug | Mechanism | Epilepsy Types | Reference |
---|---|---|---|
Potassium bromide | GABA potentiation | Generalized tonic-clonic seizures, myoclonic seizures | [53,54] |
Phenobarbital | Potentiation of GABAA receptor | Partial and generalized convulsive seizures | [55] |
Primidone | GABA potentiation | Partial and generalized convulsive seizures | [56] |
Diazepam | Potentiation of GABAA receptor | Status epilepticus | [57,58,59] |
Valproate | Multiple mechanisms with glutamate inhibition, blockade of sodium and T-type calcium channels, inhibition of GABA transaminase and re-uptake | Partial and generalized convulsive seizures, absence seizures | [60,61] |
Clonazepam | Potentiation of GABAA receptor | Juvenile myoclonic epilepsy | [62,63] |
Benzodiazepines | Potentiation of GABAA receptor | Partial and generalized convulsive seizures, Lennox–Gastaut syndrome, myoclonic seizures | [58] |
Vigabatrin | Inhibition of GABA transaminase | Infantile spasms, complex partial seizures | [64,65] |
Tiagabine | Inhibition of GABA transporter | Partial seizures | [52] |
PLC Isozyme | Animal or Human Study | Phenotype | Reference |
---|---|---|---|
PLCβ1 | Genetic knockout mice | Early-onset epileptic encephalopathy | [127] |
Mongolian gerbils mice | Increased PLCβ1 expression after seizures | [135] | |
Genetic knockout mice | Malignant migrating partial seizures in infancy | [128] | |
Pilocarpine-induced status epilepticus in mice | Decreased PLCβ1 expression in hippocampal interneurons after seizures | [136] | |
Homozygous deletions or nonsense variant in human | Infantile epileptic encephalopathy | [130] | |
PLCβ4 | Genetic knockout mice | Absence seizures | [133] |
PLCγ1 | TrkB mutation mice in PLCγ1 binding domain | Decreased pilocarpine-induced status epilepticus | [137] |
Heterozygote knockout mice | Decreased kindling-induced seizures | [138,139] | |
GABAergic neuron-specific knockout mice | Late-onset seizures | [140] |
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Kim, H.Y.; Suh, P.-G.; Kim, J.-I. The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy. Int. J. Mol. Sci. 2021, 22, 3149. https://doi.org/10.3390/ijms22063149
Kim HY, Suh P-G, Kim J-I. The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy. International Journal of Molecular Sciences. 2021; 22(6):3149. https://doi.org/10.3390/ijms22063149
Chicago/Turabian StyleKim, Hye Yun, Pann-Ghill Suh, and Jae-Ick Kim. 2021. "The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy" International Journal of Molecular Sciences 22, no. 6: 3149. https://doi.org/10.3390/ijms22063149