Organic cation permeation through the channel formed by polycystin-2.
Polycystin-2 (PC2), a member of the transient receptor potential family of ion channels (TRPP2), forms a calcium-permeable cation channel. Mutations in PC2 lead to polycystic kidney disease. From the primary sequence and by analogy with other channels in this family, PC2 is modeled to have six transmembrane domains. However, most of the structural features of PC2, such as how large the channel is and how many subunits make up the pore of the channel, are unknown. In this study, we estimated the pore size of PC2 from the permeation properties of the channel. Organic cations of increasing size were used as current carriers through the PC2 channel after PC2 was incorporated into lipid bilayers. We found that dimethylamine, triethylamine, tetraethylammonium, tetrabutylammonium, tetrapropylammonium, and tetrapentylammonium were permeable through the PC2 channel. The slope conductance of the PC2 channel decreased as the ionic diameter of the organic cation increased. For each organic cation tested, the currents were inhibited by gadolinium and anti-PC2 antibody. Using the dimensions of the largest permeant cation, the minimum pore diameter of the PC2 channel was estimated to be at least 11 A. The large pore size suggests that the primary state of this channel found in vivo is closed to avoid rundown of cation gradients across the plasma membrane and excessive calcium leak from endoplasmic reticulum stores.
Anyatonwu
Georgia I
GI
Pharmacology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Ehrlich
Barbara E
BE
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D005682:Gadolinium / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D009930:Organic Chemicals / Q000378:metabolism; D010539:Permeability; D011487:Protein Conformation; D013552:Swine; D050396:TRPP Cation Channels
D015220:Calcium Channels; D002412:Cations; D005682:Gadolinium; D008565:Membrane Proteins; D009930:Organic Chemicals; D050396:TRPP Cation Channels