# Generation of a Deep Mouse Brain Spectral Library for Transmembrane Proteome Profiling in Mental Disease Models

## TL;DR

Researchers created a detailed library of transmembrane proteins in the mouse brain to better understand mental diseases and identify new drug targets.

## Contribution

A high-quality spectral library of 3043 transmembrane proteins in mouse brain regions, enabling deeper proteomic analysis of mental disease models.

## Key findings

- The spectral library includes 171 GPCRs, 231 ion channels, and 598 transporters from various brain regions.
- A new GPCR regulator of depression was identified through in vivo pharmacological testing.
- Differential regulation of transmembrane proteins was observed in depression- and anxiety-like mouse models.

## Abstract

Transmembrane (TM) proteins constitute over 30% of the mammalian proteome and play essential roles in mediating cell-cell communication, synaptic transmission, and plasticity in the central nervous system. Many of these proteins, especially the G protein–coupled receptors (GPCRs), are validated or candidate drug targets for therapeutic development for mental diseases, yet their expression profiles are underrepresented in most global proteomic studies. Herein, we establish a brain TM protein-enriched spectral library based on 136 data-dependent acquisition runs acquired from various brain regions of both naïve mice and mental disease models. This spectral library comprises 3043 TM proteins including 171 GPCRs, 231 ion channels, and 598 transporters. Leveraging this library, we analyzed the data-independent acquisition data from different brain regions of two mouse models exhibiting depression- or anxiety-like behaviors. By integrating multiple informatics workflows and library sources, our study significantly expanded the mental stress-perturbed TM proteome landscape, from which a new GPCR regulator of depression was verified by in vivo pharmacological testing. In summary, we provide a high-quality mouse brain TM protein spectral library to largely increase the TM proteome coverage in specific brain regions, which would catalyze the discovery of new potential drug targets for the treatment of mental disorders.

•A deep mouse brain spectral library including 3043 transmembrane proteins.•Library-based DIA data analysis integrating three complementary workflows.•Differentially regulated transmembrane proteins found in two mental diseaes.•Discovery of a new potential GPCR regulator of depressive-like behaviors.

A deep mouse brain spectral library including 3043 transmembrane proteins.

Library-based DIA data analysis integrating three complementary workflows.

Differentially regulated transmembrane proteins found in two mental diseaes.

Discovery of a new potential GPCR regulator of depressive-like behaviors.

The establishment of a high-quality mouse brain transmembrane protein spectral library enables in-depth profiling of membrane receptors and other membrane proteins across various brain regions. Data-independent acquisition data analysis, combining multiple computational workflows all based on the spectral library, discovered a new regulator from the G protein–coupled receptor family which mediates depressive-like behaviors in an animal model. This library represents a valuable resource for brain transmembrane proteome mapping to facilitate the discovery of putative drug targets for treatment of psychiatric disorders.