Maintaining the equilibrium of bodily water involves a delicate interplay between water intake and excretion through processes such as urination, defecation, perspiration, and respiration. Notably, elevated levels of the antidiuretic hormone vasopressin have been observed to reduce urine volume, thereby preventing excessive loss of water from the system. The canonical pathway for this regulation occurs within the renal collecting ducts, where vasopressin triggers a sequence involving cAMP and protein kinase A (PKA) signalling. This cascade culminates in the phosphorylation of Aquaporin-2 (AQP2) water channels, facilitating the reabsorption of water from urine. While recent omics data have shed light on downstream targets influenced by PKA, the pivotal regulators that oversee PKA-induced AQP2 phosphorylation remain elusive. A primary challenge arises from the widespread application of vasopressin as a positive control to activate PKA, an approach that can induce non-specific phosphorylation across various PKA substrates due to vasopressin's potent and indiscriminate effects. The intracellular positioning of PKA is under meticulous control, largely orchestrated by specialized scaffold proteins termed A-Kinase Anchoring Proteins (AKAPs). These AKAPs possess distinct target domains dictating their precise cellular localization, thereby creating discrete PKA signalling networks. Though vasopressin typically triggers PKA activation regardless of intracellular localization, certain chemical agents selectively target PKAs situated on vesicles containing AQP2. These agents concurrently induce phosphorylation of AQP2 and its associated PKA substrates. Through immunoprecipitation coupled with mass spectrometry analysis, it was discovered that lipopolysaccharide-responsive and beige-like anchor stood proximal to AQP2 as a PKA substrate. Subsequent investigations utilizing Lrba knockout models underscored the essential role of LRBA in vasopressin-induced AQP2 phosphorylation.
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