Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Arribas-González, Esther; Juan-Sanz, Jaime de; Aragón, Carmen; López-Corcuera, Beatriz

doi:10.1074/jbc.m114.587055

Cited by 29 publications

(48 citation statements)

References 52 publications

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“…One of them, S510R, affects GlyT2 intracellular trafficking and blocks the arrival of the transporter to the plasma membrane [54]. A detailed study of the pathogenic mechanisms in mutant S512R of the rat sequence (equivalent to the human mutation S510R) indicates that the presence of an arginine residue rather than serine provokes GlyT2 misfolding, enhances its association to the ER-chaperone calnexin, alters the association with the COPII component Sec 24D and, as a consequence, impedes the exit of the transporter from the ER [57]. The S512R mutant forms oligomers with wild-type GlyT2 causing its retention in the ER and therefore the dominant negative effect.…”

Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

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Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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“…were prepared as described previously 12 . Briefly, the cortex of Wistar rat fetuses was obtained on the 18th day of gestation, and the tissue was mechanically disaggregated in Hanks' balanced salt solution (Invitrogen) containing 0.25% trypsin (Invitrogen) and 4 mg/ml DNase (Sigma).…”

Section: Primary Cultures Of Cerebral Cortex and Transfection-primarymentioning

confidence: 99%

“…Understanding the molecular regulation of GlyT2 transport would provide insight into the molecular and cellular basis of glycinergic neurotransmission and potentially lead to identifying new therapeutic targets for presynaptic Hyperekplexia. Previous studies on GlyT2 regulatory mechanisms revealed that GlyT2 activity is regulated by PKC activation 10,11 , calnexin function 12,13 , P2Y and P2X purinergic receptors 14,15 and interaction with syntaxin1 16 , Na+/K+-ATPase 17 and PMCAs 18 . In addition, we previously described that GlyT2 trafficking and surface expression are regulated by ubiquitination 11,19 , a process in which the small protein ubiquitin is covalently attached to a cytoplasmic lysine residue of a target protein.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase LNX1 is a major regulator of glycine recapture by the presynaptic transporter GlyT2

Núñez

Arribas-González

López-Corcuera

et al. 2017

Preprint

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The neuronal glycine transporter GlyT2 is an essential regulator of glycinergic neurotransmission that recaptures glycine in presynaptic terminals to facilitate quantal transmitter packaging in synaptic vesicles. Alterations in GlyT2 expression or activity result in lower cytosolic glycine levels, emptying glycinergic synaptic vesicles and impairing neurotransmission. Lack of glycinergic neurotransmission caused by GlyT2 loss-of-function mutations results in Hyperekplexia, a rare neurological disease characterized by generalized stiffness and motor alterations that may result in sudden infant death. Although the importance of GlyT2 in pathology is known, how this transporter is regulated at the molecular level is poorly understood, limiting current therapeutic strategies. Guided by an unbiased screening, we discovered that the E3 ubiquitin ligase Ligand of Numb protein X1 (LNX1) modulates the ubiquitination status of GlyT2. LNX1 ubiquitinates a cytoplasmic C-terminal lysine cluster in GlyT2 (K751, K773, K787 and K791) through its N-terminal RING-finger domain, and this process regulates the expression levels and transport activity of GlyT2 in neurons. These experiments reveal for the first time the identity of an E3 ubiquitin-ligase acting on GlyT2 and identify a novel regulatory mechanism by which neurons regulate GlyT2 expression and activity.

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“…In humans, this dysfunction is the main presynaptic cause of Hyperekplexia [7][8][9][10] , but it also may be involved in the pathology of chronic pain 11 and deficits in auditory processing 12 . A better understanding of the molecular regulation of GlyT2 would help framing future studies on the importance of this transporter in human disease and we and others have identified some molecular mechanisms controlling GlyT2 expression and activity [13][14][15][16][17][18][19][20][21][22][23] . Ubiquitination, a post-translational modification in which the small protein ubiquitin is covalently attached to a cytoplasmic lysine residue of a protein, is a major control point that finely tunes the expression of GlyT2 14,17,24,25 .…”

Section: Introductionmentioning

confidence: 99%

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

Rocha-Munoz

Nunez

Gomez-Lopez

et al. 2020

Preprint

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The identity of a glycinergic synapse is maintained presynaptically by the activity of a surface glycine transporter, GlyT2, which recaptures glycine back to presynaptic terminals to preserve vesicular glycine content. GlyT2 loss-of-function mutations cause Hyperekplexia, a rare neurological disease in which loss of glycinergic neurotransmission causes generalized stiffness and strong motor alterations. However, the molecular underpinnings controlling GlyT2 activity remain poorly understood. In this work, we identify the Hedgehog pathway as a robust controller of GlyT2 expression and transport activity. Modulating the activation state of the Hedgehog pathway in vitro in rodent primary spinal cord neurons or in vivo in zebrafish embryos induced a selective control in GlyT2 expression, regulating GlyT2 transport activity. Our results indicate that activation of Hedgehog reduces GlyT2 expression by decreasing its mRNA levels and increasing its ubiquitination and degradation. This work describes a new molecular link between the Hedgehog signaling pathway and presynaptic glycine availability.

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Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Cited by 29 publications

References 52 publications

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Ubiquitin ligase LNX1 is a major regulator of glycine recapture by the presynaptic transporter GlyT2

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

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