![]() ![]() Based on the observations that in unc-46 mutants the Vesicular GABA Transporter (VGAT) is miss-localized to non-vesicular compartments and that loading of synaptic vesicles with GABA is deficient, it was proposed that UNC-46 functions as a trafficking chaperone that targets VGAT to synaptic vesicles. Mutations in unc-46 interfere with GABA neurotransmission. elegans, unc-46, has been shown to be specifically expressed in synaptic vesicles of GABAergic neurons. Interestingly, the LAMP5 orthologue in C. In neurons, LAMP5 accumulates in distinct intracellular vesicles that do not contain any known markers of classical intracellular transport pathways and are not targeted to the endosomal/lysosomal compartment. However, in contrast to canonical members of this family, that show widespread expression, LAMP5 is, at least in rodents, strictly confined to the brain where it appears at postnatal stages coincidently with synaptogenesis. īased on sequence and structural homology LAMP5 (BAD-LAMP/C20orf103) has been classified as a LAMP-family member. Prototypic members of this family like LAMP1 and LAMP2 are widely expressed in many tissues and have been implicated in a variety of intracellular trafficking events, often, although not exclusively, associated to lysosomal transport. Lysosome Associated Membrane Proteins (LAMPs) represent a family of membrane proteins sharing sequence and structural homology. However, due to their particular properties neurons need additional and unique trafficking systems that address their specific needs. In neurons, clathrin-mediated endocytosis represents the predominant mode of synaptic vesicle protein internalization. For example, the clathrin system is widely used in plants, yeast and animals to control endocytosis and intracellular trafficking of defined targets in concert with adaptor proteins that specify the cargo. Work over the past decades demonstrated that many mechanisms managing the cellular traffic of molecules are shared between neurons and other cells. Finally, synaptic communication is not a linear transformation of an electric stimulus into neurotransmitter release, but a locally modifiable process, whose plasticity underlies learning and memory. Once at the synapse, the situation complexifies further, as neuron-to-neuron communication critically depends on efficient vesicular loading and sorting, high-speed exocytosis and rapid recycling of cellular material and neurotransmitter. This problem is particularly evident in the case of neurons where proteins, lipids and RNA have to be transported over large distances along axons or into highly complex dendritic arborizations to reach pre- or postsynaptic sites. Trafficking of cellular components in a coordinated manner represents a major challenge for all cells. ![]() Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. ![]() LAMP5 is member of the LAMP family of membrane proteins. ![]()
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