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. 2008 Mar 28:1:1.
doi: 10.3389/neuro.02.001.2008. eCollection 2008.

A critical role for glycine transporters in hyperexcitability disorders

Robert J Harvey  1 , Eloisa Carta, Brian R Pearce, Seo-Kyung Chung, Stéphane Supplisson, Mark I Rees, Kirsten Harvey
Affiliations

A critical role for glycine transporters in hyperexcitability disorders

Robert J Harvey et al. Front Mol Neurosci. .

Abstract

Defects in mammalian glycinergic neurotransmission result in a complex motor disorder characterized by neonatal hypertonia and an exaggerated startle reflex, known as hyperekplexia (OMIM 149400). This affects newborn children and is characterized by noise or touch-induced seizures that result in muscle stiffness and breath-holding episodes. Although rare, this disorder can have serious consequences, including brain damage and/or sudden infant death. The primary cause of hyperekplexia is missense and non-sense mutations in the glycine receptor (GlyR) alpha1 subunit gene (GLRA1) on chromosome 5q33.1, although we have also discovered rare mutations in the genes encoding the GlyR beta subunit (GLRB) and the GlyR clustering proteins gephyrin (GPNH) and collybistin (ARHGEF9). Recent studies of the Na(+)/Cl(-)-dependent glycine transporters GlyT1 and GlyT2 using mouse knockout models and human genetics have revealed that mutations in GlyT2 are a second major cause of hyperekplexia, while the phenotype of the GlyT1 knockout mouse resembles a devastating neurological disorder known as glycine encephalopathy (OMIM 605899). These findings highlight the importance of these transporters in regulating the levels of synaptic glycine.

Keywords: GlyT1; GlyT2; VIAAT; glycine encephalopathy; glycine transporters; hyperekplexia; startle disease.

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Figures

Figure 1
Figure 1
A model showing key proteins at mature glycinergic synapses. Postsynaptic α1β subunit GlyRs are clustered by gephyrin. Although the RhoGEF collybistin is responsible for the translocation of gephyrin to GABAergic synapses (Harvey et al., ; Papadopoulos et al., 2007), collybistin may be dispensable for GlyR clustering, since collybistin knockout mice do not exhibit developmental onset of exaggerated acoustic or tactile startle responses (Papadopoulos et al., 2007). This suggests that additional RhoGEFs involved in the synaptic localisation of gephyrin and inhibitory receptors remain to be identified. The glial glycine transporter GlyT1 removes glycine from the synaptic cleft, thereby terminating neurotransmission. By contrast, GlyT2 (which binds ULIP6 and syntenin-1) is responsible for glycine re-uptake into the nerve terminal cytosol. This in turn provides glycine for the vesicular transporter VIAAT to refill synaptic vesicles. Glycine is also synthesised by a de novo pathway involving serine hydroxymethyl transferase (SHMT). Loss of glial GlyT1 uptake may cause raised CSF and serum glycine, leading to glycine encephalopathy.
Figure 2
Figure 2
Amino acid sequence of human GlyT1 and GlyT2 indicating the revised positions of putative transmembrane (TM) domains (coloured boxes) based on the structure of the bacterial leucine transporter (LeuT) (Yamashita et al., 2005). Mutations identified in human GlyT2 in hyperekplexia (Rees et al., 2006) are indicated by black boxes. Blue triangles above the sequence indicate residues in hGlyT1 and hGlyT2 that are likely to coordinate Na+ ions based on sequence alignments with the bacterial LeuT (Yamashita et al., 2005). However, it is noteworthy that GlyT2 binds three Na+ ions, while LeuT and GlyT1 bind two, suggesting that other residues involved in Na+ co-ordination remain to be identified in GlyT2. Filled black circles above the sequences indicate residues predicted to be involved in glycine binding. Note that mutations W482R and N509S alter putative glycine and Na+ binding residues, respectively.
Figure 3
Figure 3
Distribution of GlyT1 and GlyT2 in sections from mouse E18 embryos. Note that GlyT2 immunoreactivity is mostly confined to spinal cord (Sc) and brainstem, while GlyT1 is also expressed in some higher brain regions and peripheral tissues, especially liver (L) and pancreas (P). Reproduced with permission from: F. Jursky and N. Nelson: Developmental expression of the glycine transporters GlyT1 and GlyT2 in mouse brain. Journal of Neurochemistry 67(1), 336–344 (1996), Wiley-Blackwell, Oxford, UK.
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