Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects

University of Verona, Verona, Veneto, Italy
Journal of Biological Chemistry (Impact Factor: 4.57). 10/1998; 273(40):25967-25973. DOI: 10.1074/jbc.273.40.25967


Polycystin-1 and polycystin-2 are the products ofPKD1 and PKD2, genes that are mutated in most cases of autosomal dominant polycystic kidney disease. Polycystin-2 shares ∼46% homology with
pore-forming domains of a number of cation channels. It has been suggested that polycystin-2 may function as a subunit of
an ion channel whose activity is regulated by polycystin-1. Here we report the identification of a human gene, PKDL, which encodes a new member of the polycystin protein family designated polycystin-L. Polycystin-L has 50% amino acid sequence
identity and 71% homology to polycystin-2 and has striking sequence and structural resemblance to the pore-forming α1 subunits
of Ca2+channels, suggesting that polycystin-L may function as a subunit of an ion channel. The full-length transcript of PKDL is expressed at high levels in fetal tissues, including kidney and liver, and down-regulated in adult tissues. PKDL was assigned to 10q24 by fluorescence in situ hybridization and is linked to D10S603 by radiation hybrid mapping. There is no evidence of linkage to PKDL in six ADPKD families that are unlinked toPKD1 or PKD2. The mouse homologue ofPKDL is deleted in Krd mice, a deletion mutant with defects in the kidney and eye. We propose that PKDL is an excellent candidate for as yet unmapped cystic diseases in man and animals.

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    • "ases of autosomal dominant polycystic kidney disease ( ADPKD ) , the most common form of inherited polycystic kidney disease ( Harris and Torres , 2014 ) . pkd2l1 and pkd2l2 are two homologs of the pkd2 gene identified so far ( Veldhuisen et al . , 1999 ; Wu et al . , 1998 ) but are unlikely to be directly linked to ADPKD ( Basora et al . , 2002 ; Nomura et al . , 1998 ) . Although the func - tional role of PKD2L1 is still unclear , it was suggested that PKD2L1 might be involved in sensory physiology . Indeed , PKD2L1 has a wide expression pattern especially in several brain nuclei and sensory organs such as retina , taste bud and inner ear ( Basora et al . , 2002 ; Huang et al . , 2006 ; Ishimaru et "
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    ABSTRACT: Cerebrospinal fluid contacting neurons (CSF-cNs) are found around the central canal of all vertebrates. They present a typical morphology, with a single dendrite that projects into the cavity and ends in the CSF with a protuberance. These anatomical features have led to the suggestion that CSF-cNs might have sensory functions, either by sensing CSF movement or composition, but the physiological mechanisms for any such role are unknown. This hypothesis was recently supported by the demonstration that in several vertebrate species medullo-spinal CSF-cNs selectively express Polycystic Kidney Disease 2-Like 1 proteins (PKD2L1). PKD2L1 are members of the 'transient receptor potential (TRP)' superfamily, form non-selective cationic channels of high conductance, are regulated by various stimuli including protons and are therefore suggested to act as sensory receptors. Using patch-clamp whole-cell recordings of CSF-cNs in brainstem slices obtained from wild type and mutant PKD2L1 mice, we demonstrate that spontaneously active unitary currents in CSF-cNs are due to PKD2L1 channels that are capable, with a single opening, of triggering action potentials. Thus PKD2L1 might contribute to the setting of CSF-cN spiking activity. We also reveal that CSF-cNs have the capacity of discriminating between alkalinization and acidification following activation of specific conductances (PKD2L1 vs. ASIC) generating specific responses. Altogether, this study reinforces the idea that CSF-cNs represent sensory neurons intrinsic to the central nervous system and suggests a role for PKD2L1 channels as spike generators. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015 · Neuropharmacology
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    • "Recent progress has been made in elucidating the signaling pathways in RGC dendrites involving voltage-gated Ca 2+ channels (Margolis et al., 2010), however, surprisingly little is known about expression, distribution and function of intracellular Ca 2+ channels in RGCs. We previously reported the differential distribution of IP 3 Rs in RGCs (Mafe et al., 2006), and polycystin-L and polycystin-2L2 were detected in retina (Nomura et al., 1998, Wu et al., 1998, Guo et al., 2000). The lack of knowledge on the role of polycystin-2 in the retina is surprising given the tentative association between polycystic kidney disease and macular defects in patients and experimental models (Narendran et al., 2004, Feng et al., 2009). "
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    ABSTRACT: The polycystin family of transient receptor potential (TRP) channels form Ca(2+) regulated cation channels with distinct subcellullar localizations and functions. As part of heteromultimeric channels and multi-protein complexes, polycystins control intracellular Ca(2+) signals and more generally the translation of extracellular signals and stimuli to intracellular responses. Polycystin-2 channels have been cloned from retina, but their distribution and function in retinal ganglion cells (RGCs) have not yet been established. In the present study, we determined cellular and subcellular localization as well as functional properties of polycystin-2 channels in RGCs. Polycystin-2 expression and distribution in RGCs was assessed by immunohistochemistry on vertical cryostat section of mouse retina as well as primary cultured mouse RGCs, using fluorescence microscopy. Biophysical and pharmacological properties of polycystin-2 channels isolated from primary cultured RGCs were determined using planar lipid bilayer electrophysiology. We detected polycystin-2 immunoreactivity both in the ganglion cell layer as well as in primary cultured RGCs. Subcellular analysis revealed strong cytosolic localization pattern of polycystin-2. Polycystin-2 channel current was Ca(2+) activated, had a maximum slope conductance of 114 pS, and could be blocked in a dose-dependent manner by increasing concentrations of Mg(2+). The cytosolic localization of polycystin-2 in RGCs is in accordance with its function as intracellular Ca(2+) release channel. We conclude that polycystin-2 forms functional channels in RGCs, of which biophysical and pharmacological properties are similar to polycystin-2 channels reported for other tissues and organisms. Our data suggest a potential role for polycystin-2 in RGC Ca(2+) signaling.
    Full-text · Article · Dec 2011 · Neuroscience
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    • "Orthologs in other species have recently been identified, including mouse, sea urchin, Caenorhabditis elegans, Drosophila, and yeast are involved in diverse cellular functions, such as left–right axis determination, mechanotransduction, fertilization, mating, and cell wall synthesis. Mouse TRPP3 is located in a 7-centimorgan deleted in Krd mice which display kidney and retina defects and thus may be associated with the defects (Nomura et al. 1998). More recently, TRPP3 was shown to localize to a subset of taste receptor cells in the tongue where it may play a crucial role in sour tasting and acid sensing (Huang et al. 2006; Ishimaru et al. 2006; LopezJimenez et al. 2006), and to neurons surrounding the central canal of spinal cord where it may account for the long-sought mechanism of a protondependent regulation of action potential (Huang et al. 2006). "
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    ABSTRACT: Transient receptor potential (TRP) polycystin 2 and 3 (TRPP2 and 3) are homologous members of the TRP superfamily of cation channels but have different physiological functions. TRPP2 is part of a flow sensor, and is defective in autosomal dominant polycystic kidney disease and implicated in left-right asymmetry development. TRPP3 is reported to implicate in sour tasting in bipolar cells of taste buds of the tongue and in the regulation of pH-sensitive action potential in neurons surrounding the central canal of spinal cord. TRPP3 is present in both excitable and non-excitable cells in various tissues, such as retina, brain, heart, testis, and kidney, but its common and cell type-specific functional characteristics remain largely unknown. In this study, we investigated physical and functional interactions between TRPP3 and alpha-actinin, an actin-bundling protein known to regulate several types of ion channels. We employed planer lipid bilayer electrophysiology system to study the function of TRPP3 channel that was affinity-purified from Madin-Darby canine kidney cells. Upon reconstitution in bilayer, TRPP3 exhibited cation channel activities that were substantially augmented by alpha-actinin. The TRPP3-alpha-actinin association was documented by co-immunoprecipitation using native cells and tissues, yeast two-hybrid, and in vitro binding assays. Further, TRPP3 was abundantly present in mouse brain where it associates with alpha-actinin-2. Taken together, alpha-actinin not only attaches TRPP3 to the cytoskeleton but also up-regulates TRPP3 channel function. It remains to be determined whether the TRPP3-alpha-actinin interaction is relevant to acid sensing and other functions in neuronal and non-neuronal cells.
    Full-text · Article · Jan 2008 · Journal of Neurochemistry
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