Application of Neuregulin-1 (NRG1) in preparation of product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity

A neuregulin and channel technology, applied in the field of nervous system disease treatment, can solve problems such as NRG1TRPC6 channel function not seen

Inactive Publication Date: 2020-01-24
GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Up to now, there is no research report on the effect of NRG1 on TRPC6 channel function through nitrosylation

Method used

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  • Application of Neuregulin-1 (NRG1) in preparation of product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity
  • Application of Neuregulin-1 (NRG1) in preparation of product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity
  • Application of Neuregulin-1 (NRG1) in preparation of product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] This example provides the co-labeling of TRPC6 channel protein and ErbB4 receptor of NRG1 in the hippocampal region of the brain by immunofluorescence labeling.

[0039] 1. Experimental animal feeding:

[0040] SPF grade Erbb4-TD mice: male, aged 6 weeks. The animals are raised in an SPF grade animal center. The temperature in the breeding area is generally between 25°C and 28°C, and the humidity is controlled between 40% and 70%. The animal center is cleaned regularly, animal bedding is replaced, feed is added, and SPF-grade breeding-grade feed and drinking water are freely ingested.

[0041] 2. Drugs and main reagents:

[0042] Tamoxifen was purchased from Sigma-Aldrich Company (Shanghai, China).

[0043] 3. Experimental method and specific steps:

[0044] Erbb4-TD mice were obtained by crossing Erbb4-CreERT2 and Rosa::LSL-tdTomato mice (the neurons expressing ErbB4 receptors in Erbb4-TD mice will all express red fluorescent protein at the same time, so as to comp...

Embodiment 2

[0049] In this example, Western blotting and patch clamp electrophysiology were used to detect the effect of NRG1 on the nitrosylation level of TRPC6 channel protein and the promotion of GABA release before and after NEM intervention.

[0050] 1. Experimental animal feeding: the same as in Example 1.

[0051] 2. Drugs and main reagents: cesium chloride, HEPES, EGTA, ATP-Mg, GTP-Na, sodium chloride, potassium chloride, sodium dihydrogen phosphate, magnesium sulfate, magnesium chloride, calcium chloride, sodium bicarbonate, glucose , sucrose, and NEM were purchased from Sigma-Aldrich Company (China, Shanghai); recombinant human neuregulin 1 (recombinant human NRG1-β1, rNRG1-β1) (amino acid sequence: SHLVKCAEKE KTFCVNGGEC FMVKDLSNPS RYLCKCPNEFTGDRCQNYVM ASFYKHLGIE FMEAE) was purchased from ProSpec Company ( Israel, Rehovot); QX-314, TTX, CNQX, DL-AP5 were purchased from TOCRIS (Bristol, UK).

[0052] 3. Experimental method and specific steps:

[0053] (1) Tissue sample preparat...

Embodiment 3

[0067] This example provides an example of the effect of NRG1 on GABA release before and after blocking TRPC6 channels by patch clamp electrophysiology.

[0068] 1. Experimental animal feeding: the same as in Example 1.

[0069] 2. Drugs and main reagents: cesium chloride, HEPES, EGTA, ATP-Mg, GTP-Na, sodium chloride, potassium chloride, sodium dihydrogen phosphate, magnesium sulfate, magnesium chloride, calcium chloride, sodium bicarbonate, glucose , sucrose were purchased from Sigma-Aldrich Company (China, Shanghai); rNRG1-β1 was purchased from ProSpec Company (Israel, Rehovot); QX-314, TTX, CNQX, DL-AP5 were purchased from TOCRIS Company (UK, Bristol); SKF96365 was purchased from Merck Millipore (Billerica, USA); ML-7 was purchased from MCE (Monmouth Junction, USA).

[0070] 3. Experimental method and specific steps: Take adult male C57BL / 6 mice (ordinary mice) to conduct patch clamp experiments, and the experimental operation is the same as before (Example 2). Add TRPC c...

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Abstract

The invention provides application of Neuregulin-1 (NRG1) in preparation of a product to enhance Transient Receptor Potential Cation Channel Subfamily C Member 6 (TRPC6) channel activity. The invention discovers that TRPC6 channel protein is co-labeled with ErbB4 receptor of NRG1 in hippocampus through immunofluorescence experiment; and moreover, it is further proven by Western blot that the NRG1can promote nitrosylation of the TRPC6 channel protein. Then, it is proven by whole cell patch clamp experiment that both nitrosylation inhibitors and TRPC6 channel blockers can block the NRG1-ErbB4 pathway as well as promote release of gamma aminobutyric acid (GABA); and moreover, TRPC6 channel is knocked-out on intermediate neurons expressing the ErbB4 receptor so as to block effect of the NRG1on GABA release, thereby leading to neuronal rhythmic oscillations and schizophrenia-like behavioral abnormalities. Research results of the invention show that the NRG1 can activate the TRPC6 channelby promoting nitrosylation of the TRPC6 channel protein, thereby increasing the release of the GABA.

Description

technical field [0001] The invention relates to the field of treatment of nervous system diseases, in particular to the application of neuregulin 1 in the preparation of products for enhancing TRPC6 channel activity. Background technique [0002] Classical transient receptor potential channel type 6 (Transient Receptor Potential Cation Channel Subfamily C Member 6, TRPC6) channel is a kind of non-selective cation channel, belonging to the transient receptor potential channel family (TRP). TRPC6 channels are abundantly expressed in the peripheral and nervous systems, and are mainly expressed on neurons in the central nervous system, with higher expression in the hippocampus, cortex and dorsal striatum, and are associated with schizophrenia, stroke, Alzheimer's, epilepsy and other neurological diseases are related. In the periphery, it is mainly expressed on endothelial cells, and is related to familial hereditary focal segmental glomerulosclerosis, renal failure and other di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/18A61K9/14A61K9/08A61P25/18A61P25/22A61P25/20A61P25/08A61P9/10A61P25/24A61P25/00
CPCA61K38/185A61K9/14A61K9/08A61K9/0019A61P25/18A61P25/22A61P25/20A61P25/08A61P9/10A61P25/24A61P25/00
Inventor 陈永君夏宇岑万超凡颜靖岚姚琳许能贵
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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