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Published on: September 2, 2020
RIN1 inhibited TRPV1-dependent pain sensitization in a mouse model of bone cancer pain
Yue Zhang1,2,3, Hai-Feng Jiang1,2,4, Ya-Ni Guo1,2
1School of Public Health, Gansu University of Chinese Medicine, Lanzhou, Gansu, P.R. China.
Abstract:
The Ras and Rab interactor 1 (RIN1) is a multifunctional signaling protein that has been implicated in the regulation of tumor cell migration and proliferation. Here we found that RIN1 was abundant in the dorsal root ganglia (DRG) neurons positive for transient receptor potential vanilloid 1 (TRPV1), a critical mediator of pain sensitization in patients with metastatic bone cancer. Our data showed that RIN1 interacted with TRPV1 and induced the endocytosis of TRPV1 through its guanine nucleotide exchange factor activity toward small GTPase Ras-related protein 5 (Rab5). This process limited the duration and magnitude of TRPV1-dependent acute pain responses in intact male mice. Conditioned knockout of RIN1 in the DRG neurons enhanced TRPV1 activity and led to the reflexive nociceptive sensitization and aversive pain behaviors. In mice with the bone cancer pain, we found a significant reduction of RIN1 protein level in the DRG neurons, which correlated with TRPV1 accumulation on the plasma membrane. Special rescue of RIN1 expression in the DRG neurons repressed the surface TRPV1 distribution and alleviated both the reflexive-defensive and affective-motivational aspects of bone cancer pain. Our data thus revealed an important role of RIN1 in the negative control over TRPV1-dependent pain behaviors.
Insights
Ras and Rab interactor 1 (RIN1) regulates pain by controlling the endocytosis of TRPV1. Reduced RIN1 enhances TRPV1 activity, worsening bone cancer pain, while restoring RIN1 alleviates it.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Ras and Rab interactor 1 (RIN1) is a signaling protein involved in cell migration and proliferation.
- Transient receptor potential vanilloid 1 (TRPV1) mediates pain sensitization, particularly in metastatic bone cancer.
- RIN1's role in pain modulation, especially concerning TRPV1, is not fully understood.
Purpose of the Study:
- To investigate the interaction between RIN1 and TRPV1 in pain pathways.
- To determine RIN1's function in regulating TRPV1 activity and pain responses.
- To explore RIN1's potential as a therapeutic target for bone cancer pain.
Main Methods:
- Immunohistochemistry to detect RIN1 and TRPV1 in dorsal root ganglia (DRG) neurons.
- Co-immunoprecipitation to confirm RIN1-TRPV1 interaction.
- Guanine nucleotide exchange factor assays to assess RIN1's effect on Rab5.
- Behavioral tests in mice to evaluate pain responses (acute, nociceptive sensitization, bone cancer pain).
- Conditional knockout and rescue experiments for RIN1 in DRG neurons.
Main Results:
- RIN1 interacts with TRPV1 in DRG neurons and promotes TRPV1 endocytosis via Rab5.
- Loss of RIN1 in DRG neurons increases TRPV1 surface expression, leading to enhanced pain behaviors.
- RIN1 levels are reduced in DRG neurons of mice with bone cancer pain, correlating with TRPV1 accumulation.
- Restoring RIN1 in these mice reduces surface TRPV1 and alleviates bone cancer pain.
Conclusions:
- RIN1 acts as a negative regulator of TRPV1-dependent pain.
- RIN1-mediated endocytosis of TRPV1 is crucial for limiting pain duration and intensity.
- Dysregulation of RIN1 contributes to bone cancer pain, suggesting RIN1 as a potential therapeutic target.
