Fig. 3.

Signaling pathways relating disturbed polycystin-mediated Ca²⁺ signaling to apoptotic cell death. Disruption of PC1 function leads to a phenotype with low intracellular Ca²⁺ concentration and high cAMP concentration that showed a mitogenic response towards cAMP and down-regulation of PI3-K/AKT. This provokes a profound remodeling of the relation between Ca²⁺ release and Ca²⁺ influx via an IP₃R/PC2/STIM1 protein complex. Decreased AKT signaling would strengthen the IP₃R-PC2 interaction and lead to increased IICR, translocation of STIM1 to the plasma membrane, and refilling of the ER via SOCE. AKT can also directly phosphorylate the IP₃R thereby inhibiting its activity. A decreased AKT activity in cystic cells would thereby relieve the inhibition of the IP₃R and contribute to the increase in IICR. PC2 can function as an ER Ca²⁺-leak channel and a loss of function would therefore increase the ER Ca²⁺ content and IICR. The increased IICR via these different mechanisms ultimately leads to increased Ca²⁺ transfer from the ER to the mitochondria. Mitochondrial Ca²⁺ overload is a very important determinant of Ca²⁺-dependent apoptosis. Boxed areas indicate mechanisms not shown in detail. Dotted arrows indicate still unresolved mechanisms. IP₃R-P: IP₃R phosphorylated by AKT (S²⁶⁸¹ in IP₃R1)