Chapter 3 - Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy
Section snippets
GABAA Receptors
The γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) are ligand-gated chloride (Cl−) channels that mediate major inhibitory functions in the central nervous system (CNS). Many antiepileptic drugs (AEDs) are GABAA receptor agonists, whereas GABAA receptor antagonists can be strong convulsants. Hence, GABAA receptors have been postulated to play a key role in the pathogenesis of epilepsy. In fact, mutations and variations in the genes encoding GABAA receptor subunits have been
Mutations and Genetic Variations of the GABAA Receptor
Mutations and genetic variations of GABAA receptors have been associated with epilepsy (Table 1). However, only a limited number of epilepsy types result from such mutations, which are not necessarily the direct cause of epilepsy (Kim et al., 2012, Ma et al., 2006a, Ma et al., 2006b, Xiumin et al., 2007). Nevertheless, the list of GABAA receptor mutations associated with epilepsy is expected to grow in the future. Furthermore, these GABAA receptor mutations have revealed new aspects of the
Mutations of the α Subunit
The α subunit is the requisite subunit for GABAA receptors, as it is the GABA binding site that initiates GABA-evoked potentials and forms the benzodiazepine binding site with the γ subunit. Several mutations of the genes encoding the α1 (GABRA1) and α6 (GABRA6) subunits have been identified in autosomal dominant juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), and infantile spasms (ISs).
Mutations of the β Subunit
The β subunit is considered a major subunit of the GABAA receptor and is expressed predominantly in the human brain. The β2 subtype is considered the major constituent of the GABAA receptor in the adult brain, both quantitatively and spatially. In contrast, the β3 subtype is considered a major constituent in the developing brain, which indicates an important role in the developing brain, and hence in the etiology of childhood CNS disorders (Brooks-Kayal and Pritchett, 1993). A previous
Mutations of the γ Subunit
At present, more than a dozen mutations of GABRG2, the gene that encodes the γ2 subunit, have been associated with idiopathic epilepsy; most of these mutations are associated with FS. This indicates that the γ2 subunit plays an important role in the pathomechanisms of epilepsy. In fact, the γ2 subunit is considered one of the major receptor components that allow GABAA receptors to modulate phasic or synaptic transmission (Farrant and Nusser, 2005, Olsen and Sieghart, 2008, Sieghart and Sperk,
Mutations of the δ Subunit
The δ subunit is an important constituent of the GABAA receptors mediating tonic inhibition in neurons. This is in contrast to the γ subunits that are a major component of the receptors mediating phasic inhibition (Bai et al., 2001, Saxena and MacDonald, 1994, Stell et al., 2003, Wei et al., 2003). At present, three genetic variations (E177A, R220C, and R220H) of GABRD, the gene encoding δ subunit, have been associated with epilepsy in a cohort study with 72 unrelated GGE, 65 unrelated GEFS +,
Therapeutic Implications of GABAA Receptor Mutations
Mutations of GABAA receptor subunits have been associated with GGE and FS. Furthermore, there is evidence that deficient GABAergic neurons play a crucial role in the development of epilepsy. Thus, GABA receptors are likely key players in the pathomechanisms of epilepsy. Keeping this in mind, GABAA receptors should be considered for their potential in therapeutic intervention.
Besides the mutant GABAA receptors described above, one line of evidence indicates that GABAA receptors and GABAergic
Conclusions
The GABAA receptors are one type of ion channels with genetic mutations or variations that underlie epilepsy. Contrary to the mutations of other ion channels that affect channel functions, mutations of GABAA receptor subunits show more complex pathomechanisms of epilepsy. Thus, the pathomechanisms resulting from such mutations are closely associated with cell mechanisms such as ERAD, NMD, intracellular trafficking defects, and ER stress. Thus, mutations of GABAA receptor subunits have revealed
Acknowledgment
The author thanks Dr. Jing-Qiong Kang, Vanderbilt University Medical Center, and Dr. Chritoph Lossin, Department of Neurology, School of Medicine UC Davis, for their careful and critical reading of the manuscript. This work was supported by Grant-in-Aid for Scientific Research (A) (24249060); Grant-in-Aid for Challenging Exploratory Research (25670481); Bilateral Joint Research Projects (S. H.) from Japan Society for the Promotion of Science; Grants for Scientific Research on Innovative Areas
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Gene mutations (monogenic or polygenic) are likely the main cause and result in alterations to neuronal excitability, synaptic transmission, network development (Pandolfo, 2011), in addition to altered circadian rhythms (Re et al., 2020). Most known mutations affect ion channels, including sodium (Steinlein, 2014), potassium (Maljevic and Lerche, 2014) and calcium (Gambardella and Labate, 2014) voltage-gated channels, as well as the inhibitory ionotropic GABA receptor (Hirose, 2014). The activation, inhibition, trafficking, recycling/internalization, and degradation of these ion channels and receptors are critically regulated by PTMs (Onwuli and Beltran-Alvarez, 2016; Capera et al., 2019; Pei et al., 2018).