Gating of the polycystin ion channel signaling complex in neurons and kidney cells.
Mutations in either polycystin-2 (PC2) or polycystin-1 (PC1) proteins cause severe, potentially lethal, kidney disorders and multiple extrarenal (including brain) disease phenotypes. PC2, a member of the transient receptor potential channel superfamily, and PC1, an orphan membrane receptor of largely unknown function, are thought to be part of a common signaling pathway. Here, we show that in rat sympathetic neurons and kidney cells, coassembly of full-length PC1 with PC2 forms a plasmalemmal ion channel signaling complex in which PC1 stimulation simultaneously activates PC2 ion channels and Gi/o-proteins. PC2 activation occurs through a structural rearrangement of PC1, independent of G-protein activation. Thus, PC1 acts as a prototypical membrane receptor that concordantly regulates PC2 channels and G-proteins, a bimodal mechanism that may account for the multifunctional roles of polycystin proteins in fundamental cellular processes of various cell types.
Delmas
Patrick
P
Intégration des Informations Sensorielles (UMR 6150), CNRS, Faculté de Médecine, IFR Jean Roche, Bd. P. Dramard, 13916 Marseille, Cedex 20, France. delmas.p@jean-roche.univ-mrs.fr
Nauli
Surya M
SM
Li
Xiaogang
X
Coste
Bertrand
B
Osorio
Nancy
N
Crest
Marcel
M
Brown
David A
DA
Zhou
Jing
J
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D004848:Epithelium / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D015640:Ion Channel Gating; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000166:cytology; D050396:TRPP Cation Channels
D000906:Antibodies; D015220:Calcium Channels; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D011506:Proteins; D050396:TRPP Cation Channels