Polycystins, calcium signaling, and human diseases.
Autosomal dominant polycystic kidney disease (ADPKD) is a major, inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of fluid-filled cysts from the tubules and collecting ducts of affected kidneys. The pathogenesis of cyst formation is currently thought to involve increased proliferation of epithelial cells, mild dedifferentiation, and fluid accumulation. In the past decade, study of ADPKD led to the discovery of a unique family of highly complex proteins, the polycystins. Loss-of-function mutations in either of two polycystin proteins, polycystin-1 or polycystin-2, give rise to ADPKD. These proteins are thought to function together as part of a multiprotein complex that may initiate Ca2+ signals, directing attention to the regulation of intracellular Ca2+ as a possible misstep that participates in cyst formation. Here we review what is known about the Ca2+ signaling functions of polycystin proteins and focus on findings that have significantly advanced our physiological insight. Special attention is paid to the recently discovered role of these proteins in the mechanotransduction of the renal primary cilium and the model it suggests.
Delmas
Patrick
P
Laboratoire de Neurophysiologie Cellulaire, CNRS-UMR 6150, Faculté de Médecine, IFR Jean Roche, Bd. Pierre Dramard, 13916 Marseille Cedex 20, France. delmas.p@jean-roche.univ-mrs.fr
Padilla
Françoise
F
Osorio
Nancy
N
Coste
Bertrand
B
Raoux
Matthieu
M
Crest
Marcel
M
D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling; D002923:Cilia / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D050396:TRPP Cation Channels
D015220:Calcium Channels; D008565:Membrane Proteins; D011506:Proteins; D050396:TRPP Cation Channels