Figure 9. Proposed role for NHA2 in PKD.

Polycystins 1 and 2 (PC1 and PC2) regulate Ca²⁺ influx, NFAT signalling and NHA2 expression. Methylxanthine drugs (caffeine and theophylline) activate ryanodine‐sensitive receptor channel (RyR) and release Ca²⁺ stores from the endoplasmic reticulum (ER) in response to an initial Ca²⁺ entry through PC2 and other plasma membrane Ca²⁺ channels, thereby effectively amplifying cytoplasmic Ca²⁺ and increasing NHA2 expression. Vasopressin stimulation of the V2R receptors results in accumulation of cyclic AMP (cAMP) and activation of protein kinase A (PKA). Like caffeine and theophylline, vasopressin‐driven PKA activation stimulates Ca²⁺ release via the RyR, leading to an increase NHA2 expression which is associated with cyst expansion.