The Inhibitory Glycine Receptor

The inhibitory glycine receptor (GlyR) mediates fast synaptic inhibition mainly in the brainstem and spinal cord (Betz, 1992). In higher areas of the central nervous system, this function is carried out by GABAA receptors, but both receptor systems overlap in their sites of action. They both belong to a superfamily of membrane-bound neurotrans-mitter receptors constituting ligand-gated ion channels. This family includes excitatory, acetylcholine- and serotonin-activated sodium-conducting ion channels, as well as inhibitory chloride-conducting ion channels activated by GABA and glycine (Breitinger and Becker, 2002; Grenningloh et al., 1987; Rajendra et al., 1997; Schofield, 2002; Vannier and Triller, 1997).

The members of this receptor family generally represent pentameric complexes of different subunit proteins. The subunits within this family are relatively homologous to

figure 1 Schematic drawing of the human glycine receptor ai subunit. M2 depicts the transmembrane region that forms the inside of the channel as indicated in the small scheme.

each other, and all consist of five hydrophilic regions of variable size interrupted by four transmembrane domains. Figure i depicts a schematic drawing of a typical subunit of this kind, the a1 subunit of the strychnine-sensitive glycine receptor (GlyRa1), as it is found in adult humans.

The adult GlyR in rodents as well as in humans consists of three ligand-binding a1 subunits and two structural b subunits (Kuhse et al., 1993; Langosch et al., 1988). The respective M2 transmembrane regions form the ion channel (Bormann et al., 1993) (Figure 1). Binding of the natural ligand glycine leads to gating of the channel and subsequent influx of chloride ions. Thereby hyperpolarization occurs, inhibiting neuronal firing. In addition to the natural ligand glycine, the GlyR binds and responds to several other ligands, such as the amino acids taurine and b-alanine. The alkaloid strychnine binds specifically and with high affinity to the glycine receptor as a competitive antagonist in vitro and in vivo (Pfeiffer and Betz, 1981). Acute poisoning results in severe generalized hypotonia and convulsions (Becker, 1992; Dittrich et al., 1984; Smith, 1990). Subcon-vulsive doses lead to hyperresponsiveness to sensory stimuli due to the reduction of inhibition, thereby disturbing the balance between excitatory and inhibitory signalling.

These symptoms are similar to those observed in hereditary hyperekplexia or startle disease. Analogous syndromes have been identified in other mammals, including horse (Gundlach et al., 1993), cattle (Gundlach, 1990; Pierce et al., 2001), and mouse (White and Heller, 1982). Analyses of the underlying mechanisms revealed mutations in genes of the GlyR in humans (Breitinger and Becker, 2002; Shiang et al., 1993), as well as mice (Buckwalter et al., 1994; Kingsmore et al., 1994; Mulhardt et al., 1994; Ryan et al., 1994; Saul et al., 1994), and cattle (Pierce et al., 2001). The glycine receptor structure and function is highly conserved between mammalian species, emphasizing the importance of this system in evolution.

The subunit composition of the GlyR underlies developmental and spatial variation. Early in development, a homopentamer of the neonatal a2 subunit forms the receptor complex (Becker et al., 1992), whereas a switch to the ai/ß subunit complex occurs in humans around birth (Ryan et al., 1994), and in mice 2 weeks postnatally (Becker et al., 1988; Ryan et al., 1994). In addition to a1 and a2, two more a-subunits with so far unknown function, a3 (Kuhse et al., 1990) and a4 (Matzenbach et al., 1994) exist. However, the different isoforms of the GlyRa subunit are expressed in different temporal and spatial limits (Malosio et al., 1991). Further variability is introduced by the existence of several a subunit splice variants of unknown function (Vannier and Triller, 1997). In contrast, the GlyRb-subunit, which is responsible for positioning the adult GlyR complex to the synapse through binding the cytoplasmatic anchoring protein gephyrin (Kirsch et al., 1996), does not display isoform variation. It is widely expressed in the nervous system, and the role of b subunit expression in regions without a subunit co-expression is unclear. Thus it is not known if it forms complexes with any other neurotransmit-ter subunit than GlyRai. As demonstrated by work on mouse mutants, however, GlyRa1 requires the expression of the b subunit to form the adult GlyR in animals (Kingsmore et al., 1994; Mulhardt et al., 1994).

The GlyR activity can be regulated on several levels. In addition to the ligand binding, its function can be modulated by intracellular phosphorylation of the a1 and the b subunit (Ruiz-Gomez et al., 1991; Vaello et al., 1994). Furthermore, Zn2+ ions affect receptor activity in a concentration-dependent manner (Laube et al., 2000), and several alcohols and anesthetics have been reported to modify the activity of reconstituted receptors in tissue culture and in Xenopus oocytes, whereby the potentiating effect of ethanol on GlyR function should be emphasized (Belelli et al., 1999; Mascia et al., 1998; Mascia et al., 2000; Mihic, 1999; Miller, 2002).

The molecular functions of the GlyR subunits have been investigated in many studies by mutational analyses in tissue culture or other heterologous systems. To investigate the complex interactions with other transmitter systems relevant in vivo, in hyperekplexia as well as in other diseases, mutant and transgenic animal models were analyzed.

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