MGC4618 antibody - N-terminal region (ARP34360_P050)
- Known as:
- MGC4618 (anti-) - N-terminal region (ARP34360_P050)
- Catalog number:
- arp34360_p050
- Product Quantity:
- USD
- Category:
- -
- Supplier:
- Aviva Systems Biology
- Gene target:
- MGC4618 antibody - N-terminal region (ARP34360_P050)
Related genes to: MGC4618 antibody - N-terminal region (ARP34360_P050)
- Gene:
- TMEM175 NIH gene
- Name:
- transmembrane protein 175
- Previous symbol:
- -
- Synonyms:
- MGC4618
- Chromosome:
- 4p16.3
- Locus Type:
- gene with protein product
- Date approved:
- 2006-08-29
- Date modifiied:
- 2015-09-29
Related products to: MGC4618 antibody - N-terminal region (ARP34360_P050)
Related articles to: MGC4618 antibody - N-terminal region (ARP34360_P050)
- Transmembrane protein 175 (TMEM175) is a lysosomal proton-activated and proton-selective channel critical for regulating lysosomal membrane potential and acidity. However, its role in cardiomyocyte physiological and stress response remains unclear. Here, we investigated the function of TMEM175 in mitochondrial homeostasis using H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVMs) under physiological conditions and during hydrogen peroxide (HO)-induced oxidative stress. Under physiological conditions, genetic knockout of TMEM175 impaired mitochondrial respiration, reduced mitochondrial superoxide, and attenuated autophagic clearance. In contrast, under HO-induced stress, TMEM175 deletion significantly alleviated mitochondrial dysfunction and cell death, despite autophagic flux being primarily stalled at the degradation stage. Mechanistically, TMEM175 deficiency activated AMP-activated protein kinase (AMPK), and silencing AMPK reversed the cytoprotective effects of TMEM175 deletion against HO injury. Pharmacological inhibition of TMEM175 with 2-phenylpyridin-4-ylamine (2-PPA) in H9c2 and NRVMs recapitulated key phenotypes observed in genetic knockout models. Furthermore, 2-PPA improved cardiac function and attenuated histopathological injury in myocardial infarction mice. Together, these findings reveal a dual role for TMEM175: it maintains lysosomal-mitochondrial communication under basal conditions, yet its inhibition protects against oxidative stress primarily through AMPK activation. This study identifies TMEM175 as a novel lysosomal regulator of cardiac mitochondrial resilience and highlights its potential role in the cellular response to oxidative injury in cardiomyocytes. - Source: PubMed
Publication date: 2026/08/18
Li QingliuHu NanZhao LimeiZhang ShaoxuanMeng LuluZhou JinyuLi QiujieLei FuchengYang XiaotongHu MeiqinZhu HuaHang PengzhouZhao Jing - Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage. - Source: PubMed
Publication date: 2026/08/03
Jaganathan RavindranVijayakumar SrilakshmiChen YinchiYe JiaxiBakthavatchalam PugazhandhiWankhar DapkuparYang ChuanbinIyaswamy AshokLi Min - The transmembrane protein 175 (TMEM175) is a high-risk gene for Parkinson's disease (PD) and encodes an ion channel in lysosomes. Many PD-associated variants in TMEM175 lead to the loss of ion channel function. In this study, we identified the PD-associated TMEM175-L156P variant is a missense mutation with trafficking deficiency. Using imaging, biochemical, and whole-endolysosomal electrophysiological approaches, we identified that L156P abolished the lysosomal expression of TMEM175; instead, it accumulates in the endoplasmic reticulum (ER). The cytosolic segment of the fourth transmembrane helix (TM4-1), where the L156 resides, determined the lysosomal localization of TMEM175. Having understood the structural basis, we evaluated wild-type (WT) TMEM175 and pharmacological chaperones previously used in cystic fibrosis treatment. We elucidated that WT partially rescued the aberrant expression of L156P. Moreover, the chaperones substantially reduced the ER-retained L156P and facilitated its trafficking to lysosomes. We further screened and identified a bifunctional chemical molecule that both corrected the trafficking defects and potentiated the ion channel function of L156P. Notably, the chemical-restored L156P is functional, as it relieves the lysosomal over-acidification. Conclusively, we establish the relationship between aberrant trafficking and pathogenesis in PD, demonstrating the potential of utilizing "chaperone plus agonist" bifunctional chemical molecules as personalized treatment for PD. - Source: PubMed
Publication date: 2026/07/31
Luo TingHe YuLi ShuyaoGuan HaoyuCui RuiliShi YuJiang ZhongwenWang SiyuLi XuanLi JiyuanHu MeiZhou YupengTang BeishaZhang YanyanGao ZhaobingZhou YuLiu ZhenhuaLi Ping - Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals. - Source: PubMed
Publication date: 2026/07/02
Zhang YingZhang ZhishuaiQiu ShizhengHu Yang - TMEM175 is a lysosomal cation channel essential for maintaining lysosomal pH and function. Dysregulation of TMEM175 has been implicated in Parkinson's disease, highlighting the need for small-molecule modulators to probe its physiological and therapeutic roles. We previously screened an FDA-approved compound library for TMEM175 modulators using a plasma membrane overexpression system that enables functional analysis of channel activity. Here, we report the pharmacological characterization of the most potent hit, candesartan cilexetil. In fluorescence-based thallium flux, automated patch-clamp, and manual patch-clamp assays, candesartan cilexetil robustly activates TMEM175 with efficacy comparable with the reference activator DCPIB, whereas its hydrolyzed metabolite candesartan is inactive. Candesartan cilexetil is active only when applied to the extracellular (lysosome lumen-equivalent) side of the channel and is inactive from the cytosolic-facing side. To determine whether activation requires the intact prodrug, we generated analogs that modify or eliminate the cilexetil and ester functionalities. Structure-activity studies show that selected modifications of the cilexetil moiety reduce potency while preserving maximal efficacy, whereas more extensive modification markedly reduces intrinsic activity, indicating that it is an essential pharmacophoric element rather than a simple membrane-permeating handle. Manual patch-clamp wash-off experiments further demonstrate direct, reversible activation without requiring membrane permeation or hydrolysis. Unexpectedly, the nonhydrolyzable analog VU0982645 exhibits minimal intrinsic activity yet produces robust synergistic activation with DCPIB. Together, these findings establish the cilexetil handle as a key pharmacophoric element and support synergistic modulation as a tractable mechanism for activating TMEM175. We introduce a new therapeutic paradigm for TMEM175 targeting by demonstrating that synergistic agonist pairs can drive robust channel activation. Beyond identifying candesartan cilexetil as a moderately potent activator with a previously unrecognized pharmacophoric cilexetil moiety, we show that a minimally active analog can dramatically potentiate activation in combination with DCPIB. This synergistic strategy establishes TMEM175 as a tractable therapeutic target and reveals coagonism as a powerful mechanism to modulate lysosomal ion channels. - Source: PubMed
Publication date: 2026/07/02
Li KangjunLe Samantha DSatpute Janve VaishaliLazarenko Roman MRomaine Ian MKim KwanghoSulikowski Gary AWaterson Alex GDenton Jerod S