Calcium signaling in polycystic kidney disease- cell death and survival

Abstract

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.

Keywords: ADPKD; Autophagy; Cell survival; Kidney cysts; TRP channels.

Figure 1.. Topological structure of PC-1 and PC-2.

PC-1 contains 11 transmembrane spans with a long N terminus. Domains within PC-1 N termini have been described to regulate channel activity of PC-2, a member of the Transient Receptor Potential Channel family. Red arrow indicates regions within PC-1 that have been described to regulate PC-2 channel activity. See text under Section 3.1 for details.

Figure 2.. The role of polycystin 1 and polycystin 2 in regulating signaling pathways that lead to cell death and or survival. A.

PC-1 and PC-2 have been described to interact and/or regulate molecules within the Unfolded Protein Response (UPR) which is activated by ER stress. Red arrows indicates when upon activation of ER stress there is upregulation of PC-1 or PC-2. B. Diagram of the autophagic pathways implicated in PC-1/PC-2 pathways that are activated through cell stress, calcium-dependent pathways, or hypoxia. Red spheres indicate upregulation of the indicated molecules while blue-red gradient spheres indicate contradicting data upon deletion or mutation of PC-1 or PC-2. C. Model of the regulation of the polycystin proteins in autophagy. Dash arrows indicates uncharacterized mechanism. See text under Sections 4 and 5 for details. Molecules within each panel are labeled with the corresponding color.