ArticleAmerican journal of physiology. Renal physiology2012
Forskolin stimulation promotes urea transporter UT-A1 ubiquitination, endocytosis, and degradation in MDCK cells.
Article in American journal of physiology. Renal physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 13 citations in OpenAlex.
- Tissue Distribution, Expression and Regulation of Urea Transporters.Sub-cellular biochemistry · 2025Review
- E3 ligase MDM2 mediates urea transporter-A1 ubiquitination under either constitutive or stimulatory conditions.American journal of physiology. Renal physiology · 2019Article
- Identification of UT-A1- and AQP2-interacting proteins in rat inner medullary collecting duct.American journal of physiology. Cell physiology · 2018Article
- Recruitment of endosomal signaling mediates the forskolin modulation of guinea pig cardiac neuron excitability.American journal of physiology. Cell physiology · 2017Article
- Downregulation of urea transporter UT-A1 activity by 14-3-3 protein.American journal of physiology. Renal physiology · 2015Article
- Activation of the cAMP/PKA pathway induces UT-A1 urea transporter monoubiquitination and targets it for lysosomal degradation.American journal of physiology. Renal physiology · 2013Article
- Small GTPase Rab14 down-regulates UT-A1 urea transport activity through enhanced clathrin-dependent endocytosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The adenylyl cyclase stimulator forskolin (FSK) stimulates UT-A1 phosphorylation, membrane trafficking, and urea transport activity. Here, we found that FSK stimulation induces UT-A1 ubiquitination in UT-A1 Madin-Darby canine kidney (MDCK) cells. This suggests that phosphorylation by FSK also triggers the protein degradation machinery for UT-A1. UT-A1-MDCK cells were treated with 100 μg/ml cycloheximide to inhibit protein synthesis, with or without 10 μM FSK. Total UT-A1 protein abundance was significantly reduced after FSK treatment, concomitantly ubiquitinated UT-A1 was increased. We then specifically investigated the effect of FSK on UT-A1 expressed on the cell plasma membrane. FSK treatment accelerated UT-A1 removal from the cell plasma membrane by increasing UT-A1 endocytosis as judged by biotinylation/MesNa treatment and confocal microscopy. We further found that inhibition of the clathrin-mediated endocytic pathway, but not the caveolin-mediated endocytic pathway, significantly blocks FSK-stimulated UT-A1 endocytosis. The PKA inhibitor H89 and the proteasome inhibitors MG132 and lactacystin reduced FSK-induced membrane UT-A1 reduction. Our study shows that FSK activates the UT-A1 urea transporter and the activation/phosphorylation subsequently triggers the downregulation of UT-A1, which represents an important mechanism for the cell to return to the basal conditions after vasopressin stimulation.
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