Tyrosine Phosphatase Function in Neural Synaptic Plasticity

Protein tyrosine phosphatases constitute a family of enzymes that remove phosphate groups from tyrosine residues on key signalling proteins, thus acting in opposition to protein tyrosine kinases. Within the central nervous system, one of the most extensively studied members is the striatal-enriched protein tyrosine phosphatase (STEP), which modulates the phosphorylation status of synaptic receptors and intracellular kinases critical for both long-term potentiation and long-term depression. By dephosphorylating N-methyl-D-aspartate receptor (NMDAR) subunits and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, STEP promotes receptor internalisation and attenuates synaptic strengthening. Conversely, tight regulation of STEP activity ensures that excitatory synapses can adapt during learning and memory processes. Dysregulation of tyrosine phosphatase activity has been implicated in a spectrum of neuropsychiatric and neurodegenerative disorders, where imbalanced phosphorylation leads to aberrant receptor trafficking, impaired synaptic function and cognitive deficits. Ongoing research seeks to delineate the precise mechanisms by which tyrosine dephosphorylation orchestrates synaptic homeostasis and to exploit this pathway for therapeutic intervention.

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Tyrosine Phosphatase Function in Neural Synaptic Plasticity publication trend

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Technical terms

Tyrosine phosphatase: An enzyme that catalyses removal of phosphate groups from tyrosine residues on proteins, reversing kinase actions.

Synaptic plasticity: The capacity of synapses to strengthen or weaken over time, in response to increases or decreases in activity.

Striatal-enriched protein tyrosine phosphatase (STEP): A brain-specific tyrosine phosphatase that regulates synaptic receptor trafficking and intracellular kinase signalling.

N-methyl-D-aspartate receptor (NMDAR): A subtype of glutamate receptor that mediates calcium influx and is essential for activity-dependent synaptic strengthening.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR): A fast-acting ionotropic glutamate receptor responsible for the majority of excitatory synaptic transmission.

Dephosphorylation: The enzymatic removal of a phosphate group from a protein, often resulting in altered activity or localisation.

References

1. Functional Interaction between Adenosine A2A and mGlu5 Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGlu5R Binding in Mouse Hippocampus and Neuroblastoma Cell Line. Biomolecules (2023).
2. Role of Striatal‐Enriched Tyrosine Phosphatase in Neuronal Function. Neural Plasticity (2016).
3. Molecular underpinnings of neurodegenerative disorders: striatal-enriched protein tyrosine phosphatase signaling and synaptic plasticity. F1000Research (2016).
4. The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer’s Disease and Other Neurological Disorders. Frontiers in Cell and Developmental Biology (2021).
5. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease. PLOS Biology (2014).
6. Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Molecular Brain (2015).
7. Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP). International Journal of Molecular Sciences (2021).