Adenylyl cyclase 6 in acid-base balance – adding complexity

Systemic acid-base balance is tightly controlled within a narrow range of pH. Disturbances in systemic acid-base homeostasis are associated with diverse detrimental effects. The kidney is a key regulator of acid-base balance, capable of excreting HCO₃⁻ or H⁺, and chronic kidney disease invariably leads to acidosis. However, the regulatory pathways underlying the fine-tuned acid-base sensing and regulatory mechanisms are still incompletely understood. In the article published recently in Clinical Science (vol 132 (16) 1779-1796), Poulson and colleagues investigated the role of adenylyl cyclase 6 (AC6) in acid-base homeostasis. They uncovered a complex role of AC6, specifically affecting acid-base balance during HCO₃⁻ load, which causes pronounced alkalosis in AC6-deficient mice. However, the phenotype of AC6-deficient mice appears much more complex, involving systemic effects associated with increased energy expenditure. These observations remind us that there is much to be learned about the intricate signaling pathways involved in renal control of acid-base balance and the complex ramifications of acid-base regulation.