The in vivo roles of PKD1L3 and PKD2L1 in sour taste detection

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DESCRIPTION (provided by applicant): TRP channels are implicated as necessary signaling components in various sensory systems of diverse animal species. Among TRP related genes, PKD1 and PKD2 are two major causative genes for autosomal dominant polycystic kidney disease. We have recently identified two PKD-like proteins, PKD1L3 and PKD2L1, as candidate mammalian sour receptors functioning in taste reception. PKD1L3 and PKD2L1 are coexpressed in a subset of taste receptor cells distinct from those taste cells having receptors for bitter, sweet or umami (savory) tasting chemicals. We found that PKD1L3 and PKD2L1 form a protein complex and coexpression of PKD1L3 and PKD2L1 is necessary for their functional cell surface expression. Finally, our data indicated that when coexpressed in heterologous cells, PKD1L3 and PKD2L1 are activated by various acids, but not by other classes of taste chemicals, osmolarity, or mechanical flow, suggesting that PKD1L3 and PKD2L1 function as sour taste receptors. Based on these and other findings, we propose the following projects to elucidate the in vivo function of the PKD family members. First, we will generate gene knockout mice for PKD1L3 and PKD2L1. We have completed creating a gene knockout vector for PKD2L1 and we are at the final step in creating a gene knockout vector for PKD1L3. Second, we will start analyzing the function of PKD1L3 and PKD2L1 in sour taste detection. We will analyze the homozygous and heterozygous transgenic mice using histological examinations, gustatory nerve recordings and behavioral taste tests. Third, we will generate PKD1L3 and PKD2L1 double gene knockout mice. Autosomal dominant polycistic kidney disease (ADPKD) is a genetic disorder with two major causative genes, PKD1 and PKD2. Recently we have identified two PKD-like proteins, PKD1L3 and PKD2L1, as acid receptors functioning in taste reception in mammals. The relevance of our studies to the public is that it will shed light on how PKD related proteins function as sensors for extracellular stimuli and may help develop a way to prevent ADPKD from being developed