Molecular Regulation of Polycystin TRP Channels

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive renal failure and can be caused by variants in the PKD2 genes which encode the polycystin-2 transient receptor ion channel (TRP). Despite our strong understanding of the genetic basis of ADPKD, we still do not know how polycystin-2 ion channel function is molecularly regulated. This basic question remains outstanding because polycystin-2 localizes to primary cilium—an antenna-like organelle that requires innovative tools to study. Recently, our lab achieved the first heterologous and native electrophysiological characterization of polycystin-2 in the primary cilia membrane. With our collaborators, we also published the first high-resolution structure of this channel, which has provided a molecular context for understanding ADPKD-causing variants. We have interrogated multiple mutations within three structural domains within polycystin-2 and assessed their impact on the opening and closing of the ion conductive pore, the oligomictic stability of the tetrameric channel and their trafficking to the primary cilia membrane. Our results provide a biophysical framework for understanding of polycystin-2's molecular regulation. Based on these structural observations, we propose mechanistic hypotheses regarding the impact variants found within these domains.