Elucidation of pathology and drug development for PKA-related diseases

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02933
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ando Fumiaki 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (80804559)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: PKA / AKAP / LRBA / ZNF185 / 水恒常性 / 先天性腎性尿崩症 / 血管透過性

Outline of Final Research Achievements

Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. Over 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration. PKA activation by AKAPs-PKA disruptors is a novel screening strategy to uncover responsible AKAPs for AQP2 phosphorylation. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). LRBA was colocalized with AQP2 on the same vesicles in vivo, and AQP2 phosphorylation via vasopressin / cAMP / PKA signaling was severely impaired in Lrba knockout mice, leading to the defective AQP2 trafficking to the apical plasma membrane.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

AKAPに結合するPKAは尿濃縮薬開発の標的分子として着目されてきたが、数々のAKAPの中で、LRBAが尿濃縮に最も重要であることを明らかにした。LRBAは免疫チェックポイント分子であるCTLA-4などの重要なタンパクの膜輸送にも関わっており、腎臓におけるLRBAの詳細な役割を明らかにできたことで、LRBA研究のさらなる発展につながることが期待される。