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Structural basis of TRPV5 regulation by physiological and pathophysiological modulators

Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca(2+)-selective ion channel that plays a key role in Ca(2+) homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) and inhibition by Ca(2+)-bound calmodulin...

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Autores principales: Fluck, Edwin C., Yazici, Aysenur Torun, Rohacs, Tibor, Moiseenkova-Bell, Vera Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088182/
https://www.ncbi.nlm.nih.gov/pubmed/35476976
http://dx.doi.org/10.1016/j.celrep.2022.110737
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author Fluck, Edwin C.
Yazici, Aysenur Torun
Rohacs, Tibor
Moiseenkova-Bell, Vera Y.
author_facet Fluck, Edwin C.
Yazici, Aysenur Torun
Rohacs, Tibor
Moiseenkova-Bell, Vera Y.
author_sort Fluck, Edwin C.
collection PubMed
description Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca(2+)-selective ion channel that plays a key role in Ca(2+) homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) and inhibition by Ca(2+)-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca(2+) homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P(2) activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P(2) is the primary modulator of channel gating, yet PKA controls TRPV5 activity by preventing CaM binding and channel inactivation. Our data provide detailed molecular mechanisms for regulation of TRPV5 by two key extrinsic modulators, low pH and PKA.
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spelling pubmed-90881822022-05-10 Structural basis of TRPV5 regulation by physiological and pathophysiological modulators Fluck, Edwin C. Yazici, Aysenur Torun Rohacs, Tibor Moiseenkova-Bell, Vera Y. Cell Rep Article Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca(2+)-selective ion channel that plays a key role in Ca(2+) homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) and inhibition by Ca(2+)-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca(2+) homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P(2) activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P(2) is the primary modulator of channel gating, yet PKA controls TRPV5 activity by preventing CaM binding and channel inactivation. Our data provide detailed molecular mechanisms for regulation of TRPV5 by two key extrinsic modulators, low pH and PKA. 2022-04-26 /pmc/articles/PMC9088182/ /pubmed/35476976 http://dx.doi.org/10.1016/j.celrep.2022.110737 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Fluck, Edwin C.
Yazici, Aysenur Torun
Rohacs, Tibor
Moiseenkova-Bell, Vera Y.
Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title_full Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title_fullStr Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title_full_unstemmed Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title_short Structural basis of TRPV5 regulation by physiological and pathophysiological modulators
title_sort structural basis of trpv5 regulation by physiological and pathophysiological modulators
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088182/
https://www.ncbi.nlm.nih.gov/pubmed/35476976
http://dx.doi.org/10.1016/j.celrep.2022.110737
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