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Protein tyrosine kinase-mediated potentiation of currents from cloned NMDA receptors
1Department of Biological Sciences, Laboratory for Molecular Biology, University of Illinois at Chicago, 60607-7060, USA.
Abstract:
Although serine/threonine phosphorylation has been more commonly recognized as a mechanism to modulate the function of ion channels and receptors, tyrosine phosphorylation is under increasing scrutiny. An important subtype of glutamate receptor, the NMDA receptor, is shown to be regulated by insulin via protein tyrosine kinase (PTK). NMDA currents through cloned receptors are potentiated by insulin in a subunit-specific manner. The insulin-mediated potentiation of NMDA current is diminished by inhibitors of PTKs. At least one exogenous cytosolic PTK, pp60c-src, is also able to potentiate NMDA current. Because later application of PTK inhibitors can reverse the seemingly stable insulin-mediated potentiation of NMDA current, it appears that tyrosine residues responsible for potentiation are continually rephosphorylated by some long-term PTK activity that was induced via insulin treatment.
Insights
Insulin enhances NMDA receptor activity through tyrosine phosphorylation by protein tyrosine kinases (PTKs). This effect is subunit-specific and requires ongoing PTK activity for sustained potentiation of NMDA currents.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- Serine/threonine phosphorylation is a known regulator of ion channels and receptors.
- Tyrosine phosphorylation is increasingly recognized for its role in cellular regulation.
Purpose of the Study:
- To investigate the role of tyrosine phosphorylation in regulating NMDA receptor function.
- To determine the effect of insulin on NMDA receptor activity via protein tyrosine kinases (PTKs).
Main Methods:
- Utilized cloned NMDA receptors to study insulin-mediated potentiation.
- Employed PTK inhibitors to assess the role of tyrosine phosphorylation.
- Investigated the effect of exogenous PTK (pp60c-src) on NMDA currents.
Main Results:
- Insulin potentiates NMDA currents in a subunit-specific manner.
- PTK inhibitors diminish insulin-mediated potentiation of NMDA currents.
- Exogenous PTK (pp60c-src) also potentiates NMDA current.
- Sustained potentiation requires continuous PTK activity, indicating ongoing rephosphorylation.
Conclusions:
- Insulin regulates NMDA receptor function through PTK-mediated tyrosine phosphorylation.
- Tyrosine phosphorylation is a critical mechanism for modulating NMDA receptor activity.
- The potentiation effect is dynamic and dependent on sustained PTK signaling.