Distinct protein domains regulate ciliary targeting and function of C. elegans PKD-2.
TRPP2 (transient receptor potential polycystin-2) channels function in a range of cells where they are localized to specific subcellular regions including the endoplasmic reticulum (ER) and primary cilium. In humans, TRPP2/PC-2 mutations severely compromise kidney function and cause autosomal dominant polycystic kidney disease (ADPKD). The Caenorhabditis elegans TRPP2 homolog, PKD-2, is restricted to the somatodendritic (cell body and dendrite) and ciliary compartments of male specific sensory neurons. Within these neurons PKD-2 function is required for sensation. To understand the mechanisms regulating TRPP2 subcellular distribution and activity, we performed in vivo structure-function-localization studies using C. elegans as a model system. Our data demonstrate that somatodendritic and ciliary targeting requires the transmembrane (TM) region of PKD-2 and that the PKD-2 cytosolic termini regulate subcellular distribution and function. Within neuronal cell bodies, PKD-2 colocalizes with the OSM-9 TRP vanilloid (TRPV) channel, suggesting that these TRPP and TRPV channels may function in a common process. When human TRPP2/PC-2 is heterologously expressed in transgenic C. elegans animals, PC-2 does not visibly localize to cilia but does partially rescue pkd-2 null mutant defects, suggesting that human PC-2 and PKD-2 are functional homologs.
Knobel
Karla M
KM
University of Wisconsin School of Pharmacy, Division of Pharmaceutical Sciences; 777 Highland Avenue Madison WI 53705, USA.
Peden
Erik M
EM
Barr
Maureen M
MM
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism* / Q000502:physiology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000378:metabolism*; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D009419:Nerve Tissue Proteins; D050396:TRPP Cation Channels; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C108820:OSM-9 protein, C elegans; C527777:PKD-2 protein, C elegans