Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD.

ABSTRACT

Polycystin 2 (PC2) is one of two main protein types responsible for the underlying etiology of autosomal dominant polycystic kidney disease (ADPKD), the most prevalent monogenic renal disease in the world. This debilitating and currently incurable condition is caused by loss-of-function mutations in PKD2 and PKD1, the genes encoding for PC2 and Polycystin 1 (PC1), respectively. Two-hit mutation events in these genes lead to renal cyst formation and eventual kidney failure, the main hallmarks of ADPKD. Though much is known concerning the physiological consequences and dysfunctional signaling mechanisms resulting from ADPKD development, to best understand the requirement of PC2 in maintaining organ homeostasis, it is important to recognize how PC2 acts under normal conditions. As such, an array of work has been performed characterizing the endogenous function of PC2, revealing it to be a member of the transient receptor potential (TRP) channel family of proteins. As a TRP protein, PC2 is a nonselective, cation-permeant, calcium-sensitive channel expressed in all tissue types, where it localizes primarily on the endoplasmic reticulum (ER), primary cilia, and plasma membrane. In addition to its channel function, PC2 interacts with and acts as a regulator of a number of other channels, ultimately further affecting intracellular signaling and leading to dysfunction in its absence. In this review, we describe the biophysical and physiological properties of PC2 as a cation channel and modulator of intracellular calcium channels, along with how these properties are altered in ADPKD.