Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Abstract

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.

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

“…GlyT2 function is essential to sustain glycinergic neurotransmission strength in vertebrates 3,4,6 and its dysfunction causes Hyperekplexia, a rare disease characterized by hypertonia and pronounced startle responses to stimuli that can cause sudden infant death 6,36,81 . In this work, we identify a novel molecular link between the activation status of the Hedgehog pathway and the function of GlyT2.…”

“…Studies in zebrafish also described that GlyT2 appears early in development at 20-24 hours post-fertilization (hpf) and presents its maximum expression at 4-5 days post fertilization in the dorsal region, when primary spinal cord neurogenesis appears complete 40,41 . These data suggest that GlyT2 may have an early role in establishing the identity of inhibitory glycinergic synapses 38 in addition to its well-established role in sustaining glycinergic neurotransmission strength in the mature CNS 3,[35][36][37] . Although GlyT2 developmental expression pattern is relatively well described and some transcription factors have been involved in its early appearance in spinal cord 42,43 , the signaling pathways that may control this process remain unknown.…”

“…GlyT2 expression is necessary for establishing and maintaining the identity of a glycinergic synapse 3,[35][36][37] . During development, GlyT2 expression in mice increases during synaptogenesis and precedes the appearance of the α1 subunit isoform of the adult glycine receptor (GlyR) 38,39 , which mediates the activity switch of the GlyR from depolarizing to hyperpolarizing that it is required for a functional inhibitory glycinergic synapse 36 . Studies in zebrafish also described that GlyT2 appears early in development at 20-24 hours post-fertilization (hpf) and presents its maximum expression at 4-5 days post fertilization in the dorsal region, when primary spinal cord neurogenesis appears complete 40,41 .…”

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

“…Glycine transport activity of GlyT2 depends on the availability of the transporter at the neuronal surface and, in fact, regulation of surface expression is a common regulatory mechanism in the solute carrier (SLC) family of transporters to control transport rates of a wide array of substrates across biological membranes of neurons 15,[52][53][54][55] . Glycine transport by GlyT2 is essential for maintaining diverse aspects of motor function and impairment of its activity causes important pathologies in humans, from movement disorders to sensory dysfunctions 9 . To better understand the functional relevance of LNX1-mediated control of GlyT2 expression in transport activity, we next explored to what extent LNX1 expression may impact glycine recapture using [ 3 H]-glycine uptake assays in COS7 cells and primary neurons.…”

“…In humans, this dysfunction is the main presynaptic cause of Hyperekplexia [3][4][5][6] , but may also result in chronic pain 7 and deficits in auditory processing 8 . Although the importance of GlyT2-mediated glycine transport in pathology is known 2,6,9 , our knowledge on how the activity of this transporter is regulated is currently limited. 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.…”