Application of AKAPs-PKA disruptors in the treatment of PKA-related diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H01049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Uchida Shinichi 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50262184)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: protein kinase A / AKAPs / AKAPs-PKA結合阻害 / 先天性腎性尿崩症 / 肥満症

Outline of Final Research Achievements

Vasopressin / cAMP / protein kinase A (PKA) / AQP2 water channels signaling pathway regulates body water homeostasis in kidneys. Loss-of-function mutations in the vasopressin type 2 receptor cause congenital nephrogenic diabetes insipidus (NDI) characterized by defective urine concentration. We focused on direct PKA activators as a novel therapeutic target for congenital NDI. A low molecular weight compound FMP-API-1/27 dissociates interactions between PKA and its anchoring proteins (AKAPs) and then directly activates PKA in renal collecting ducts. Among various AKAP-PKA interactions, FMP-API-1/27 specifically dissociated the LRB-PKA interaction. Lrba knockout mice displayed polyuric phenotype, with severely impaired AQP2 phosphorylation. We next promoted further development of derivatives of FMP-API-1/27 in terms of pharmacological potency. We synthesized compounds that had an antidiuretic effect via oral administration.

Free Research Field

腎臓内科学関連

Academic Significance and Societal Importance of the Research Achievements

LRBAは腎臓集合管においてAQP2の膜輸送を制御していた。LRBAはT細胞においてCTLA4受容体の膜輸送を制御することが知られており、免疫と尿濃縮において類似の膜輸送機構が存在すると考えられた。LRBAの機能不全は免疫不全症を引き起こすが、Lrba KOマウスには免疫不全の表現型がないことから生体内のLRBA機能を詳細に解析することが困難である。今後、腎臓におけるLRBA機能を解析することにより膜輸送の新しい基本原理の解明が期待できる。AKAP-PKA結合阻害剤は既存薬には無い新たなカテゴリーのPKA活性制御剤であり、化合物の分子標的を明らかにすることで新規研究分野の開拓が可能になる。