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Enhanced retinal insulin receptor-activated neuroprotective survival signal in mice lacking the protein-tyrosine
Raju V S Rajala1, Masaki Tanito, Benjamin G Neel
1Department of Ophthalmology, Dean A McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Abstract:
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated in the negative regulation of insulin signaling. We previously demonstrated that light-induced tyrosine phosphorylation of the retinal insulin receptor (IR) results in the activation of phosphoinositide 3-kinase/Akt survival pathway in rod photoreceptor cells. The molecular mechanism behind light-induced activation of IR is not known. We investigated the in vivo mechanism of IR activation and found that PTP1B activity in dark-adapted retinas was significantly higher than in light-adapted retinas. We made a novel finding in this study that the light-dependent regulation of PTP1B activity is signaled through photobleaching of rhodopsin. Conditional deletion of PTP1B in rod photoreceptors by the Cre-loxP system resulted in enhanced IR signaling. Further PTP1B activity negatively regulated the neuroprotective survival signaling in the retina. One of the challenging questions in the retina research is how mutations in human rhodopsin gene slowly disable and eventually disrupt photoreceptor functions. Our studies suggest that a defect in the photobleaching of rhodopsin and mutation in rhodopsin gene enhances the activity of PTP1B, and this activated activity could down-regulate the IR survival signaling. Our studies suggest that PTP1B antagonists could be potential therapeutic agents to treat stress-induced photoreceptor degenerations and provide further evidence that rhodopsin photoexcitation may trigger signaling events alternative to the classic phototransduction.
Insights
Light exposure reduces protein-tyrosine phosphatase 1B (PTP1B) activity in the retina, protecting insulin receptor (IR) signaling. PTP1B antagonists may treat photoreceptor degeneration.
Area of Science:
- Retinal cell biology
- Molecular signaling pathways
- Neuroscience
Background:
- Protein-tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling.
- Light-induced insulin receptor (IR) activation in rod photoreceptors involves the phosphoinositide 3-kinase/Akt pathway.
- The precise mechanism of light-induced IR activation remains unclear.
Purpose of the Study:
- To elucidate the in vivo mechanism of light-induced IR activation in the retina.
- To investigate the role of PTP1B in regulating IR signaling in response to light.
- To explore the potential therapeutic implications of targeting PTP1B in retinal degeneration.
Main Methods:
- Measurement of PTP1B activity in dark-adapted versus light-adapted retinas.
- Utilizing a Cre-loxP system for conditional deletion of PTP1B in rod photoreceptors.
- Assessment of IR signaling and survival pathways in genetically modified retinas.
Main Results:
- PTP1B activity is significantly higher in dark-adapted retinas compared to light-adapted retinas.
- Light-dependent regulation of PTP1B activity is mediated by rhodopsin photobleaching.
- Conditional deletion of PTP1B in rod photoreceptors enhances IR signaling and neuroprotective pathways.
- Elevated PTP1B activity negatively impacts retinal survival signaling.
Conclusions:
- Rhodopsin photobleaching is a key regulator of PTP1B activity in the retina.
- PTP1B acts as a negative regulator of IR survival signaling in photoreceptor cells.
- Defects in rhodopsin photobleaching or mutations may lead to increased PTP1B activity, contributing to photoreceptor dysfunction.
- PTP1B antagonists represent a potential therapeutic strategy for stress-induced photoreceptor degenerations.
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