LRBA is essential for urinary concentration and body water homeostasis

被引:11
|
作者
Hara, Yu [1 ]
Ando, Fumiaki [1 ]
Oikawa, Daisuke [2 ]
Ichimura, Koichiro [3 ]
Yanagawa, Hideki [1 ]
Sakamaki, Yuriko [4 ]
Nanamatsu, Azuma [1 ]
Fujiki, Tamami [1 ]
Mori, Shuichi [5 ]
Suzuki, Soichiro [1 ]
Yui, Naofumi [1 ]
Mandai, Shintaro [1 ]
Susa, Koichiro [1 ]
Mori, Takayasu [1 ]
Sohara, Eisei [1 ]
Rai, Tatemitsu [1 ]
Takahashi, Mikiko [6 ]
Sasaki, Sei [7 ,8 ]
Kagechika, Hiroyuki [5 ]
Tokunaga, Fuminori [2 ]
Uchida, Shinichi [1 ]
机构
[1] Tokyo Med & Dent Univ, Dept Nephrol, Tokyo 1138510, Japan
[2] Osaka Metropolitan Univ, Grad Sch Med, Dept Med Biochem, Osaka 5458585, Japan
[3] Juntendo Univ, Dept Anat & Life Struct, Grad Sch Med, Tokyo 1138421, Japan
[4] Tokyo Med & Dent Univ, Res Core, Tokyo 1138510, Japan
[5] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Tokyo 1010062, Japan
[6] Teikyo Heisei Univ, Fac Pharmaceut Sci, Tokyo 1648530, Japan
[7] Tokyo Med & Dent Univ, Adv Res Inst, Tokyo 1138501, Japan
[8] Cellular & Struct Physiol Industrious Agcy, Chiyoda Ku, 2-1-1 Otemachi, Tokyo 1000004, Japan
基金
日本学术振兴会;
关键词
LRBA; AQP2; PKA; AKAP; urinary concentration; PHOSPHORYLATION; AQUAPORIN-2; MEMBRANE; PHOSPHODIESTERASE; IDENTIFICATION; EXPRESSION; PHENOTYPE; BINDING; MICE; DEFICIENCY;
D O I
10.1073/pnas.2202125119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:10
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