Molecular mechanisms of antiseizure drug activity at GABAA receptors

Abstract

The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic "tone" by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for "GABAergic" ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention.

Keywords: Antiepileptic drugs; Chloride channel; Epilepsy; GABA receptor; Inhibition; Seizures.

Figure 1

Model of a GABA_A receptor in the plasma membrane. A. A space-filling model of the pentomer in side view (A) and top view (B) based on the high sequence homology with the nicotinic acetylcholine receptor. There are with two binding sites for GABA, between α and β subunits (bent arrows), and one for BZs between the alpha and gamma subunits (arrow). C. A schematic view shows the topology of each subunit with a large extracellular loop containing a cysteine loop and 4 transmembrane domains (M1-M4), the second of which forms the chloride ion channel. Binding of GABA allows the channel to open and conduct Cl⁻ ions, resulting in the fast inhibitory post-synaptic potential (IPSP). D. Putative arrangement of 5 subunits to form a pentamer with central chloride channel lined by the M2 subunit. [Derived from the published structure: RCSB PDB Database·PDB ID: 2BG9 from Unwin, N. (2005). Images modified from en.wikipedia.org/wiki/GABA_A_receptor, used with permission (public domain)].

Figure 2

Model of a prototype GABA_AR subunit (based on α1 subunit diagram from Olsen & Tobin, 1990) showing approximate locations of point mutations associated with generalized epilepsies (see also Macdonald et al., 2012 ) in black, and locations of point mutations associated with ASD sites of action. See text for details.