LRBA is essential for urinary concentration and body water homeostasis

Author:

Hara Yu1ORCID,Ando Fumiaki1,Oikawa Daisuke2ORCID,Ichimura Koichiro3,Yanagawa Hideki1,Sakamaki Yuriko4,Nanamatsu Azuma1ORCID,Fujiki Tamami1ORCID,Mori Shuichi5,Suzuki Soichiro1,Yui Naofumi1,Mandai Shintaro1ORCID,Susa Koichiro1,Mori Takayasu1,Sohara Eisei1ORCID,Rai Tatemitsu1,Takahashi Mikiko6ORCID,Sasaki Sei78,Kagechika Hiroyuki5ORCID,Tokunaga Fuminori2,Uchida Shinichi1

Affiliation:

1. Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

2. Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan

3. Department of Anatomy and Life Structure, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan

4. Research Core, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

5. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan

6. Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo 164-8530, Japan

7. Advanced Research Institute, Tokyo Medical and Dental University, Tokyo 113-8501, Japan

8. Cellular and Structural Physiology Industrious Agency, 2-1-1, Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan

Abstract

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. More than 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 several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were nearly perfectly correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We found that LRBA colocalized with AQP2 in vivo, and Lrba knockout mice displayed a polyuric phenotype with severely impaired AQP2 phosphorylation. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts. Furthermore, the LRBA–PKA interaction, rather than other AKAP–PKA interactions, was robustly dissociated by PKA activation. AKAP–PKA interaction inhibitors have attracted attention for their ability to directly phosphorylate AQP2. Therefore, the LRBA–PKA interaction is a promising drug target for the development of anti-aquaretics.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

TMDU Young Innovative Medical Scientist Unit

Uehara Memorial Foundation

Takeda Science Foundation

Pharmacodynamics Research Foundation

Japan Intractable Diseases (Nanbyo) Research Foundation

MSD Life Science Foundation, Public Interest Incorporated Foundation

TMDU priority research areas grant

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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