更新于：2024-05-01

ATP4A

ATPase H+/K+ transporting subunit alpha

更新于：2024-05-01

基本信息

别名

ATP4A、ATP6A、ATPase H+/K+ transporting alpha subunit

+ [7]

简介

The catalytic subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells. Uses ATP as an energy source to pump H(+) ions to the gastric lumen while transporting K(+) ion from the lumen into the cell (By similarity). Remarkably generates a million-fold proton gradient across the gastric parietal cell membrane, acidifying the gastric juice down to pH 1 (By similarity). Within a transport cycle, the transfer of a H(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing (E1) to outward-facing state (E2). The release of the H(+) ion in the stomach lumen is followed by binding of K(+) ion converting the pump conformation back to the E1 state (By similarity).

关联

100 项与 ATP4A 相关的临床结果

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100 项与 ATP4A 相关的转化医学

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0 项与 ATP4A 相关的专利（医药）

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项与 ATP4A 相关的文献（医药）

2024-01-16·Translational psychiatry

Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor.

Article

作者: Hikari Hatakama ; Nozomi Asaoka ; Kazuki Nagayasu ; Hisashi Shirakawa ; Shuji Kaneko

Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D₂ receptor (D₂R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D₂R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.

2023-11-14·Journal of gastroenterology

Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation.

Article

作者: Chihiro Takeuchi ; Junichi Sato ; Nobutake Yamamichi ; Natsuko Kageyama-Yahara ; Akiko Sasaki ; Takemi Akahane ; Rika Aoki ; Shigemi Nakajima ; Masayoshi Ito ; Mitsue Yamamichi ; Yu-Yu Liu ; Nobuyuki Sakuma ; Yu Takahashi ; Yoshiki Sakaguchi ; Yosuke Tsuji ; Kouhei Sakurai ; Shuta Tomida ; Keiko Niimi ; Toshikazu Ushijima ; Mitsuhiro Fujishiro

BACKGROUND:

Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms.

METHODS:

A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression.

RESULTS:

Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach.

CONCLUSIONS:

AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.

2023-08-27·Molecular and cellular biochemistry

Identified and potential internalization signals involved in trafficking and regulation of Na⁺/K⁺ ATPase activity.

Review

作者: Rawad Hodeify ; Sawsan Kreydiyyeh ; Leen Mohammad Jamal Zaid

The sodium-potassium pump (NKA) or Na⁺/K⁺ ATPase consumes around 30-40% of the total energy expenditure of the animal cell on the generation of the sodium and potassium electrochemical gradients that regulate various electrolyte and nutrient transport processes. The vital role of this protein entails proper spatial and temporal regulation of its activity through modulatory mechanisms involving its expression, localization, enzymatic activity, and protein-protein interactions. The residence of the NKA at the plasma membrane is compulsory for its action as an antiporter. Despite the huge body of literature reporting on its trafficking between the cell membrane and intracellular compartments, the mechanisms controlling the trafficking process are by far the least understood. Among the molecular determinants of the plasma membrane proteins trafficking are intrinsic sequence-based endocytic motifs. In this review, we (i) summarize previous reports linking the regulation of Na⁺/K⁺ ATPase trafficking and/or plasma membrane residence to its activity, with particular emphasis on the endocytic signals in the Na⁺/K⁺ ATPase alpha-subunit, (ii) map additional potential internalization signals within Na⁺/K⁺ ATPase catalytic alpha-subunit, based on canonical and noncanonical endocytic motifs reported in the literature, (iii) pinpoint known and potential phosphorylation sites associated with NKA trafficking, (iv) highlight our recent studies on Na⁺/K⁺ ATPase trafficking and PGE2-mediated Na⁺/K⁺ ATPase modulation in intestine, liver, and kidney cells.

项与 ATP4A 相关的新闻（医药）

2023-06-04

·医药地理

2022年获批进口药品分析（消化系统、血液和造血、内分泌及代谢）

本文数据来自于CPM新药研发监测数据库（cpm.pharmadl.com）。消化系统用药2022年NMPA批准的进口消化系统用药，共计22个（按照注册证号分类），获批品种前三的企业分别为阿斯利康（6个）、Minophagen Pharm（4个）、IPSEN Consumer HealthCare（3个）；涉及最多的靶点是ATP4A（6个）。在政策相关度方面，2022年获批的进口消化系统用药中，没有2022国家医保目录品种，带量采购招标品种共有14个。血液和造血系统用药2022年NMPA批准的进口血液和造血系统用药，共计52个（按照注册证号分类），获批品种前三的企业分别是拜耳（5个）、费森尤斯卡比（4个）、辉瑞（4个）、武田（4个）、百特（4个）。涉及靶点排名前三的是F10（10个）、F8（8个）、P2RY12（4个）。在政策相关度方面，2022年获批的进口血液和造血系统用药中，2022国家医保目录品种共有38个，没有带量采购招标品种。内分泌及代谢调节用药2022年NMPA批准的进口内分泌及代谢调节用药，共计39个（按照注册证号分类），获批品种前五的几家企业分别为诺和诺德（8个）、赛诺菲（6个）、诺华（5个）。涉及靶点排名前三的是INSR（8个）、GLP1R（6个）、GHR（3个）。在政策相关度方面，2022年获批的进口内分泌及代谢调节用药中，2022国家医保目录品种共有38个，没有带量采购招标品种。年度发布2023年《全球药研新动态》《中国医院市场用药格局》（2023版）2023年《数图药讯》权威发布2021年度中国医药工业百强榜单解读中国仿制药发展报告（2022版）医药行业专项报告中国医药中间体和原料药行业调研报告中国非甾体抗炎类原料药市场调研报告中国祛痰类原料药市场调研报告中国钙拮抗剂类原料药市场调研报告中国血管紧张素Ⅱ受体拮抗剂类原料药市场调研报告中国口服血糖调节类原料药市场调研报告中国中枢兴奋类原料药市场调研报告中国抗痛风类原料药市场调研报告中国脑血管病类原料药市场调研报告END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

带量采购

2021-10-18

·Endpoints

Phathom's old Takeda drug bests Prevacid in a PhIII GI trial. Next stop? The FDA

There’s no time for rest in biopharma — at least not at Phathom Pharmaceuticals. Just over a month after submitting two NDAs for its lead acid-fighter vonoprazan, the biotech is already lining up a third, and collecting an extra $50 million to push things along. Vonoprazan met its primary non-inferiority endpoints in a Phase III study comparing it to standard-of-care Prevacid in a type of gastroesophageal reflux disease (GERD) called erosive esophagitis (EE). It also proved superior to the popular heartburn drug by multiple measures, including healing rate and maintenance of healing. “The results further solidify vonoprazan’s potential to be the first major innovation in the U.S. and European GERD market in more than 30 years,” CEO Terrie Curran said in a statement. Phathom Pharmaceuticals has come a long way since it was spun out of Takeda, with the help of Frazier, two years ago to handle the ex-Japan development of vonoprazan. Vonoprazan, discovered by Takeda, is a P-CAB: a class of drugs that blocks the potassium-binding site of gastric hydrogen potassium ATPase (also known as the proton pump), which is the enzyme largely responsible for acidification of the stomach. It’s already approved in Japan to treat a variety of acid-related conditions, including EE. The Phase III Phalcon-EE trial enrolled just over 1,000 EE patients in the US and Europe, who were treated with a 20 mg dose of vonoprazan in a healing phase and one of two doses (10 mg or 20 mg) in a maintenance phase. In the healing phase, vonoprazan proved non-inferior to Prevacid in terms of patients who achieved complete healing by Week 8, with a healing rate of 93% in the vonoprazan arm compared to 85% in the Prevacid arm (p<0.0001). It also passed an exploratory superiority test, with a p-value of 0.0001. Patients on vonoprazan saw significantly faster healing in this phase. However, a superiority test comparing a 20 mg dose of vonoprazan to a 30 mg dose of Prevacid for sustained resolution of heartburn by Day 3 did not turn up statistically significant (p=0.2196). Vonoprazan met the primary and all secondary endpoints in the maintenance phase, though, demonstrating superiority in maintenance of healing (79% for vonoprazan 10 mg, 81% for vonoprazan 20 mg, and 72% for Prevacid). The p-values there were less than 0.0001 for both non-inferiority comparisons, 0.0218 for the 10 mg superiority test and 0.0068 for the 20 mg superiority test. Both vonoprazan doses also achieved superiority in the percentage of patients with moderate-to-severe disease who maintained healing of EE through Week 24 (75% for vonoprazan 10 mg, 77% for vonoprazan 20 mg, and 61% for Prevacid). The frequency of serious adverse events were roughly the same in the 20 mg vonoprazan and Prevacid arms of the healing phase, but about twice as high in the 20 mg vonoprazan arm of the maintenance phase, according to Phathom. However, that does include five patients in the 20 mg arm who got Covid-19, which was unrelated to the treatment. The new data will allow Phathom to submit an NDA in the first half of next year, and triggers an extra $50 million from its term loan facility with Hercules Capital. It’s also good news for Catalent, which inked a deal to manufacture the drug just a few weeks ago.