Vasopressin kontrolliert die Proteinmenge des Wasserkanals Aquaporin-2 durch Hemmung des proteosomalen Abbaus

In the inner medullary collecting duct (IMCD) cells of the kidney, aquaporin-2 (AQP2) translocates from intracellular vesicles to the apical plasma membrane following hormonal stimulation by arginine-vasopressin (AVP). The membrane insertion facilitates water resorption from tubular fluid (primary urine) and fine-tunes body water homeostasis. AVP binds to the vasopressin type 2 receptors (V2R), initiating an intracellular signaling pathway in which the activation of protein kinase A (PKA) by cyclic adenosine monophosphate (cAMP) leads to the phosphorylation of AQP2, e.g., an increase in serine-256 phosphorylation. In addition, AVP causes activation of the transcription factor CRE (cAMP responsive element) and increased transcription of the AQP2-encoding gene. While AQP2 transport takes place in seconds, the activation of CRE and transcription takes several hours. Using in vitro and in vivo models, the present study shows the presence of a third, previously undescribed, mechanism of AQP2 regulation. An increase in cAMP concentration in IMCD cells following stimulation by AVP or Forskolin (FSK), a direct activator of adenylyl cyclases, led to an increase in AQP2 protein abundance by more than 60 percent within 30 minutes. As a mechanism explaining this observation, the inhibition of proteosomal degradation of AQP2 was identified. The inhibition occurs as a result of AVP-mediated activation of PKA and consequent inhibition of the proteasomal degradation of AQP2. The mechanism is independent of phosphorylation of AQP2 at S256 and of translation and transcription of the AQP2 gene. Diseases resulting from inadequate water homeostasis leading to either excessive water excretion (diabetes insipidus) or excessive water retention (end-stage congestive heart failure, liver cirrhosis or SIADH (Syndrome of inappropriate antidiuretic hormone)) continue to present many clinical challenges due to a lack of pharmacological treatment options. The findings of this study could aid the development of pharmacological strategies for the treatment of water balance disorders by targeting the metabolism of AQP2.

Author dc:creator

• Beulshausen, Sven

• Aquaporin-2
• inhibition
• protesomal degradation
• intracellular protein abdundance

Licence dc:rights.uri

• http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen

Language dc:language

ger

Identifier URI

http://dx.doi.org/10.17169/refubium-31726

OAI record oai:identifier

https://refubium.fu-berlin.de/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arefubium.fu-berlin.de%3Afub188%2F31995