Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1442-50. doi: 10.1152/ajprenal.00212.2013. Epub 2014 Apr 16.

Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Hall, G., Rowell, J., Farinelli, F., Gbadegesin, R. A., Lavin, P., Wu, G., Homstad, A., Malone, A., Lindsey, T., Jiang, R., Spurney, R., Tomaselli, G. F., Kass, D. A., Winn, M. P.,
["Division of Nephrology, Duke University Medical Center, Durham, North Carolina; Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;", "Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;", "Division of Nephrology, Duke University Medical Center, Durham, North Carolina; Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina; and.", "Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland.", "Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Division of Nephrology, Duke University Medical Center, Durham, North Carolina; Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;", "Division of Nephrology, Duke University Medical Center, Durham, North Carolina;", "Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;", "Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;", "Division of Nephrology, Duke University Medical Center, Durham, North Carolina; Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; michelle.winn@duke.edu."]
The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr(69)/Thr(70) (Thr(69) in mice and Thr(70) in humans) and Ser(321)/Ser(322) (Ser(321) in mice and Ser(322) in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr(69) in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30-60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG (P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso-N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41-2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3',4'-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr(69) dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30-60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.
PMID: 24740790External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Functional consequence Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPC6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 Calcineurin In vivo PTM assay Dephosphorylation 24740790
TRPC6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PKG1 In vivo PTM assay Phosphorylation (Thr-69) 24740790
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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