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Renal unresponsiveness to the antidiuretic hormone vasopressin impairs aquaporin-2 (AQP2) water channel activity and water reabsorption from urine, resulting in polyuria. Currently available symptomatic treatments inadequately reduce patients\u2019 excessive amounts of urine excretion, threatening their quality of life. In the past 25\u00a0years, vasopressin\/cyclic adenosine monophosphate (cAMP)\/protein kinase A (PKA) has been believed to be the most important signaling pathway for AQP2 activation. Although cAMP production without vasopressin is the reasonable therapeutic strategy for congenital NDI caused by V2R mutations, the efficacy of candidate drugs on AQP2 activation is far less than that of vasopressin.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Intracellular distribution and activity of PKA are largely controlled by its scaffold proteins, A-kinase anchoring proteins (AKAPs). Dissociating the binding of AKAPs and PKA significantly increased PKA activity in the renal collecting ducts and activated AQP2 phosphorylation and trafficking. Remarkably, the AKAPs\u2013PKA disruptor FMP-API-1 increased transcellular water permeability in isolated renal collecting ducts to the same extent as vasopressin. Moreover, derivatives of FMP-API-1 possessed much more high potency. FMP-API-1\/27 is the first low-molecular-weight compound to be discovered that can phosphorylate AQP2 more effectively than preexisting drug candidates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>AKAP-PKA disruptors are a promising therapeutic target for congenital NDI. In this article, we shall discuss the pathophysiological roles of PKA and novel strategies to activate PKA in renal collecting ducts.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10157-021-02108-6","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T12:03:42Z","timestamp":1625486622000},"page":"1051-1056","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Activation of AQP2 water channels by protein kinase A: therapeutic strategies for congenital nephrogenic diabetes insipidus"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8401-1705","authenticated-orcid":false,"given":"Fumiaki","family":"Ando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"issue":"6412","key":"2108_CR1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/361549a0","volume":"361","author":"K Fushimi","year":"1993","unstructured":"Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S. 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