leading to a rise in intracellular cAMP, ultimately resulting in phosphorylation of AQP2 at serine 256 by cAMP-dependent protein kinase [9] and its redistribution to the plasma membrane.
The importance of AQP2 redistribution has been highlighted by functional characterization of Aqp2 mutations resulting in severe NDI in humans [3,10]. Recessive Aqp2 mutations are generally thought to produce an abnormally localized and, in most instances, misfolded water pore that responds abnormally to an increase in cAMP [6,11]. Furthermore, dominant mutations have been described and found to misroute both the mutant and the wild-type protein to the basolateral membrane [6,12].
Several mouse models of diabetes insipidus have been generated [13–17]. In an attempt to recapitulate human NDI, mice have been generated with mutations in Aqp2 and Avpr2 [15,18]. Yang and colleagues created a mouse with a T126M knock-in mutation in the Aqp2 gene. Unexpectedly, homozygous mutant mice died within 6 d after bi