Masahiro Ikeda1, William B Guggino. 1. Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Abstract
PURPOSE OF REVIEW: During the past 2 years growing evidence has emerged that polycystins (polycystin-1 and polycystin-2) are ion channels or regulators of ion channels. This suggests that autosomal-dominant polycystic kidney disease (ADPKD), which arises from mutations in polycystins, is a form of ion-channel disease (channelopathy). The present review addresses the properties and the mode of action of polycystin channels; it also discusses how polycystin channel signaling may be involved in cyst formation in ADPKD. RECENT FINDINGS: The precise functions of polycystin-1 and polycystin-2 are unclear. However, recent work has revealed that polycystin-1 may induce or modulate ion channels, including polycystin-2 channels, and that polycystin-2 functions as a calcium-regulated, calcium-permeable cation channel on the endoplasmic reticulum or on the plasma membrane with polycystin-1. These data suggest that ion-channel signaling mediated by polycystins is important for tubule formation in kidney and that disrupted signaling results in cyst formation. SUMMARY: ADPKD is a systemic hereditary disease that is characterized by renal and hepatic cysts, and results in end-stage renal failure in 50% of affected individuals. Most cases (>95%) are caused by genetic mutations in either the PKD1 or the PKD2 gene, or both, which encode polycystin-1 and polycystin-2, respectively. The present review provides a hint of how malfunction of polycystins may give rise to cysts, based on recent observations concerning polycystin channels. Polycystin channel signaling may prove to be an important new target for therapy of ADPKD.
PURPOSE OF REVIEW: During the past 2 years growing evidence has emerged that polycystins (polycystin-1 and polycystin-2) are ion channels or regulators of ion channels. This suggests that autosomal-dominant polycystic kidney disease (ADPKD), which arises from mutations in polycystins, is a form of ion-channel disease (channelopathy). The present review addresses the properties and the mode of action of polycystin channels; it also discusses how polycystin channel signaling may be involved in cyst formation in ADPKD. RECENT FINDINGS: The precise functions of polycystin-1 and polycystin-2 are unclear. However, recent work has revealed that polycystin-1 may induce or modulate ion channels, including polycystin-2 channels, and that polycystin-2 functions as a calcium-regulated, calcium-permeable cation channel on the endoplasmic reticulum or on the plasma membrane with polycystin-1. These data suggest that ion-channel signaling mediated by polycystins is important for tubule formation in kidney and that disrupted signaling results in cyst formation. SUMMARY: ADPKD is a systemic hereditary disease that is characterized by renal and hepatic cysts, and results in end-stage renal failure in 50% of affected individuals. Most cases (>95%) are caused by genetic mutations in either the PKD1 or the PKD2 gene, or both, which encode polycystin-1 and polycystin-2, respectively. The present review provides a hint of how malfunction of polycystins may give rise to cysts, based on recent observations concerning polycystin channels. Polycystin channel signaling may prove to be an important new target for therapy of ADPKD.