Journal article
WNK4 Kinase Stimulates Caveola-mediated Endocytosis of TRPV5 Amplifying the Dynamic Range of Regulation of the Channel by Protein Kinase C
The Journal of biological chemistry, Vol.285(9), pp.6604-6611
02/26/2010
DOI: 10.1074/jbc.M109.056044
PMCID: PMC2825456
PMID: 20061383
Abstract
WNK4 (
w
ith-
n
o-lysine (
K
) kinase-
4
) is present in the distal nephron of the kidney and plays an important role in the regulation of renal ion transport. The epithelial Ca
2+
channel TRPV5 (
t
ransient
r
eceptor
p
otential
v
anilloid
5
) is the gatekeeper of transcellular Ca
2+
reabsorption in the distal nephron. Previously, we reported that activation of protein kinase C (PKC) increases cell-surface abundance of TRPV5 by inhibiting caveola-mediated endocytosis of the channel. Here, we report that WNK4 decreases cell-surface abundance of TRPV5 by enhancing its endocytosis. Deletion analysis revealed that stimulation of endocytosis of TRPV5 involves amino acids outside the kinase domain of WNK4. We also investigated interplay between WNK4 and PKC regulation of TRPV5. The maximal level of TRPV5 current density stimulated by the PKC activator 1-oleoyl-acetyl-
sn
-glycerol (OAG) is the same with or without WNK4. The relative increase of TRPV5 current stimulated by OAG, however, is greater in the presence of WNK4 compared with that without WNK4 (∼215% increase
versus
60% increase above the level without OAG). Moreover, the rate of increase of TRPV5 by OAG is faster with WNK4 than without WNK4. The enhanced increase of TRPV5 in the presence of WNK4 is also observed when PKC is activated by parathyroid hormones. Thus, WNK4 exerts tonic inhibition of TRPV5 by stimulating caveola-mediated endocytosis. The lower basal TRPV5 level in the presence of WNK4 allows amplification of the stimulation of channel by PKC. This interaction between WNK4 and PKC regulation of TRPV5 may be important for physiological regulation of renal Ca
2+
reabsorption by parathyroid hormones or the tissue kallikrein
in vivo
.
Details
- Title: Subtitle
- WNK4 Kinase Stimulates Caveola-mediated Endocytosis of TRPV5 Amplifying the Dynamic Range of Regulation of the Channel by Protein Kinase C
- Creators
- Seung-Kuy Cha - From theChou-Long Huang - From the
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.285(9), pp.6604-6611
- DOI
- 10.1074/jbc.M109.056044
- PMID
- 20061383
- PMCID
- PMC2825456
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology
- Grant note
- DK-20543; DK-85726 / National Institutes of Health
- Language
- English
- Date published
- 02/26/2010
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094662702771
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