International Journal of Molecular Sciences Review The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy Hye Yun Kim 1, Pann-Ghill Suh 1,2 and Jae-Ick Kim 1,* 1 Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea; [email protected] (H.Y.K.); [email protected] (P.-G.S.) 2 Korea Brain Research Institute (KBRI), Daegu 41062, Korea * Correspondence: [email protected]; Tel.: +82-52-217-2458 Abstract: Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy. Citation: Kim, H.Y.; Suh, P.-G.; Kim, J.-I. The Role of Phospholipase C in Keywords: Phospholipase C (PLC); γ-aminobutyric acid (GABA); excitatory/inhibitory balance (E/I GABAergic Inhibition and Its balance); GABAergic inhibition; epilepsy Relevance to Epilepsy. Int. J. Mol. Sci. 2021, 22, 3149. https://doi.org/ 10.3390/ijms22063149 1. Introduction Academic Editor: Epilepsy, one of the most common neurological disorders, is characterized by re- Giangennaro Coppola peated spontaneous seizures with abnormal hyperexcitation and synchronous discharge of neurons [1]. Approximately 60 million people worldwide suffer from epilepsy with Received: 29 November 2020 cognitive and psychiatric comorbidities [2,3]. Although several biological factors have Accepted: 17 March 2021 Published: 19 March 2021 been identified as an etiology of epilepsy, including genetic mutation, brain injury, tumor, and aging, the precise cause of epilepsy in most cases is still unknown [4,5]. One of the hy- Publisher’s Note: MDPI stays neutral potheses explaining the pathophysiological mechanism of epilepsy is that the disruption of with regard to jurisdictional claims in excitation and inhibition balance (E/I balance) could generally lead to abnormal excitability published maps and institutional affil- of neurons [6–8]. In the brain, neurons receive numerous excitatory and inhibitory synaptic iations. inputs and once the synaptic potentials in dendrites and soma are integrated together, neurons produce axon potentials with various shapes, rates, and patterns of firing [9]. E/I balance either by increasing excitation or decreasing inhibition is associated with the hyperexcitation of neurons, which can cause epileptic seizures [7,10,11]. γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. using GABA, GABAergic inhibitory neurons primarily regulate the excitability of neurons. This article is an open access article GABAergic neurons produce GABA from glutamate using glutamic acid decarboxylase distributed under the terms and (GAD) and this synthesized GABA is packaged into synaptic vesicles at synaptic terminals conditions of the Creative Commons through vesicular GABA transporters (VGATs). Synaptically released GABA binds to both Attribution (CC BY) license (https:// presynaptic and postsynaptic GABA receptors (GABAA and GABAB) and suppresses the creativecommons.org/licenses/by/ excitation of presynaptic terminals and postsynaptic neurons. In addition, the uptake 4.0/). of released GABA at GABAergic synapses is mediated by GABA transporters (GATs). Int. J. Mol. Sci. 2021, 22, 3149. https://doi.org/10.3390/ijms22063149 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2021, 22, 3149 2 of 17 the uptake of released GABA at GABAergic synapses is mediated by GABA transporters Molecular(GATs). Molecular and cellular and abnormalitiescellular abnormalities of GABA of synthesis,GABA synthesis, release, release, uptake, uptake, and GABA and receptor-mediatedGABA receptor-mediated signaling signaling can alter can E/I alter balance E/I balance in neurons in neurons and and the the dysfunctions dysfunctions of anyof any of of these these processes processes may may be be implicated implicated in in neurological neurological disordersdisorders includingincluding epilepsy, schizophrenia, and autism [[1212–1414]].. As a matter of fact,fact, thethe therapeutictherapeutic rationalerationale ofof thethe majority ofof currentcurrent antiepilepticantiepileptic drugsdrugs (AEDs)(AEDs) isis toto restorerestore alteredaltered E/I E/I balance by elevating thethe levellevel ofof GABAGABA atat synapsessynapses and and potentiating potentiating the the functions functions of of GABA GABA receptors. receptors. Hence, Hence, a bettera better understanding understanding of of the the underlying underlying molecular molecular mechanisms mechanisms thatthat regulateregulate GABAergicGABAergic inhibitioninhibition inin thethe brain brain will will be be crucial crucial to to identify identify new new drug drug targets, targets, as wellas well as toas increase to increase the efficacythe efficacy and and minimize minimize the sidethe side effects effects of antiepileptic of antiepileptic drugs. drugs. Phospholipase CC (PLC)(PLC) is is an an essential essential enzyme enzyme in intracellularin intracellular signal signal transduction transduction cas- cadescascades (Figure (Figure1). PLC 1). PLC hydrolyzes hydrolyzes phosphatidylinositol phosphatidylinositol 4,5-bisphosphate 4,5-bisphosphate (PIP 2(PIP), generating2), gener- secondaryating seconda signalry signal transducers transducers including including inositol inositol 1,4,5-triphosphate 1,4,5-triphosphate (IP3) and (IP diacylglycerol3) and diacyl- (DAG).glycerol IP (DAG).3 increases IP3 increases intracellular intracellular calcium calcium level by level binding by binding to IP3 receptors to IP3 receptors in the endo-in the plasmicendoplasmic reticulum reticulum and DAGand DAG activates activates protein protein kinase kinase C (PKC)-related C (PKC)-related signaling signaling cascades. cas- Throughoutcades. Throughout the body, the PLC body, is PLC associated is associated with key with cellular key cellular processes processes such as such proliferation, as prolif- differentiation,eration, differentiation, migration, migration, and survival and [survival15–18]. There [15–18] are. There in total are 13 in mammalian total 13 mammalian isozymes ofisozymes PLC including of PLC includingβ (1–4), γ β(1, (1 2),–4),δ γ(1, (1, 3, 2), 4), δ" (1,, ζ ,3, and 4), ε,η (1,ζ, and 2), whichη (1, 2), are wh classifiedich are classified accord- ingaccording to their to distinct their distinct domain domain structures structures and biochemical and biochemical properties. properties. Each PLC Each isozyme PLC iso- is differentiallyzyme is differentially expressed expressed among tissues among and tissues regulates and regulates the complex the complex cellular functionscellular func- in a tissue-dependenttions in a tissue-dependent manner. Among manner. these Among PLC isozymes,these PLC PLCisozymes,β and PLCPLCβγ areand major PLCγ PLC are enzymesmajor PLC abundantly enzymes abundantly expressed inexpressed the brain in and the playbrain diverse and play roles diverse in neuronal roles in functions. neuronal Infunctions. this review In this article, review we summarizearticle, we summarize the molecular the and molecular cellular and mechanisms cellular mechanisms of GABAergic of inhibitionGABAergic on inhibition the regulation on the of regulation E/I balance. of E/I Then balance. we particularly Then we particularly focus on the focus role of on PLC the inrole GABAergic of PLC in inhibition.GABAergic Finally, inhibition. we discuss Finally, the we potential discuss relationship the potential between relationship PLC and be- epilepsy.tween PLC and epilepsy. FigureFigure 1.1. The principalprincipal PLCPLC signalingsignaling cascadescascades andand functionsfunctions inin thethe brain.brain. External ligandsligands such asas neurotransmitters andand neurotrophic factors bind to and activate the upstream transmembrane receptors of PLC. PLCβ is activated by Gαq and neurotrophic factors bind to and activate the upstream transmembrane receptors of PLC. PLCβ is activated by Gαq and Gβγ subunits of G protein-coupled receptors (GPCRs), whereas the activation of PLCγ is triggered by the phosphorylation Gβγ subunits of G protein-coupled receptors (GPCRs), whereas the activation of PLCγ is triggered by the phosphorylation of receptor tyrosine kinases (RTKs). Activation of PLC hydrolyzes phospholipid PIP2 into IP3 and DAG and these second ofmessengers receptor tyrosine mediate kinases diverse (RTKs). neuronal Activation functions.