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Tonic NMDA receptor signalling shapes endosomal organisation in mammalian cells.

ABSTRACT: Calcium signalling through NMDA-type glutamate receptors (NMDARs) plays a key role in synaptic plasticity in the central nervous system (CNS). NMDAR expression has also been detected in other tissues and aberrant glutamate signalling has been linked to cancer; however, the significance of NMDAR function outside of the CNS remains unclear. Here, I show that removal of extracellular calcium rapidly decreases the size of early endosomes in primary human fibroblasts. This effect can be mimicked by blockade of NMDA-type glutamate receptors but not voltage-gated calcium channels (VGCCs), and can also be observed in primary hippocampal neurons and Jurkat T cells. Conversely, in a breast cancer cell line MDA-MB-231 NMDAR blockade results in an increase in endosomal size and decrease in number. These findings reveal that calcium signalling via glutamate receptors controls the structure of the endosomal system and suggest that aberrations in NMDAR-regulated membrane trafficking may be associated with cancer.

SUBMITTER: Glebov OO

PROVIDER: S-EPMC7283358 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Tonic NMDA receptor signalling shapes endosomal organisation in mammalian cells.

Glebov Oleg O OO

Scientific reports 20200609 1

Calcium signalling through NMDA-type glutamate receptors (NMDARs) plays a key role in synaptic plasticity in the central nervous system (CNS). NMDAR expression has also been detected in other tissues and aberrant glutamate signalling has been linked to cancer; however, the significance of NMDAR function outside of the CNS remains unclear. Here, I show that removal of extracellular calcium rapidly decreases the size of early endosomes in primary human fibroblasts. This effect can be mimicked by b ...[more]

PMID: 32518335

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Project description:BackgroundGlutamate gated postsynaptic receptors in the central nervous system (CNS) are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N-methyl-D-aspartate (NMDA) receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticityResultsThe vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure.ConclusionWe highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of the NR2 C-terminus and its associated signalling complex may contribute to species differences in behaviour and in particular cognitive function.

Dataset Information

Tonic NMDA receptor signalling shapes endosomal organisation in mammalian cells.

Publications

Tonic NMDA receptor signalling shapes endosomal organisation in mammalian cells.

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