Calcium signaling in polycystic kidney disease- cell death and survival.

Polycystic kidney disease is typified by cysts in the kidney and extra-renal manifestations including hypertension and heart failure. The main genetic underpinning this disease are loss-of function mutations to the two polycystin proteins, polycystin 1 and polycystin 2. Molecularly, the disease is characterized by changes in multiple signaling pathways including down regulation of calcium signaling, which, in part, is contributed by the calcium permeant properties of polycystin 2. These signaling pathways enable the cystic cells to survive and avoid cell death. This review focuses on the studies that have emerged in the past 5 years describing how the structural insights gained from PC-1 and PC-2 inform the calcium dependent molecular pathways of autophagy and the unfolded protein response that are regulated by the polycystin proteins and how it leads to cell survival and/or cell death.

Polycystin-2 (PC2) is a key determinant of in vitro myogenesis.

The development of skeletal muscle (myogenesis) is a well-orchestrated process where myoblasts withdraw from the cell cycle and differentiate into myotubes. Signaling by fluxes in intracellular calcium (Ca2+) is known to contribute to myogenesis, and increased mitochondrial biogenesis is required to meet the metabolic demand of mature myotubes. However, gaps remain in the understanding of how intracellular Ca2+ signals can govern myogenesis. Polycystin-2 (PC2 or TRPP1) is a nonselective cation channel permeable to Ca2+. It can interact with intracellular calcium channels to control Ca2+ release and concurrently modulates mitochondrial function and remodeling. Due to these features, we hypothesized that PC2 is a central protein in mediating both the intracellular Ca2+ responses and mitochondrial changes seen in myogenesis. To test this hypothesis, we created CRISPR/Cas9 knockout (KO) C2C12 murine myoblast cell lines. PC2 KO cells were unable to differentiate into myotubes, had impaired spontaneous Ca2+ oscillations, and did not develop depolarization-evoked Ca2+ transients. The autophagic-associated pathway beclin-1 was downregulated in PC2 KO cells, and direct activation of the autophagic pathway resulted in decreased mitochondrial remodeling. Re-expression of full-length PC2, but not a calcium channel dead pathologic mutant, restored the differentiation phenotype and increased the expression of mitochondrial proteins. Our results establish that PC2 is a novel regulator of in vitro myogenesis by integrating PC2-dependent Ca2+ signals and metabolic pathways.