Structural basis of TRPV5 regulation by physiological and pathophysiological modulators

Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca2+-selective ion channel that plays a key role in Ca2+ homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and inhibition by Ca2+-bound calmodulin (CaM). P...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2022-04, Vol.39 (4), p.110737-110737, Article 110737
Main Authors: Fluck, Edwin C., Yazici, Aysenur Torun, Rohacs, Tibor, Moiseenkova-Bell, Vera Y.
Format: Article
Language:English
Subjects:
Calcium - metabolism
Calcium Signaling
calmodulin
Calmodulin - metabolism
CaM
cryo-EM
Cryoelectron Microscopy
Cyclic AMP-Dependent Protein Kinases - metabolism
Parathyroid Hormone
PI(4,5)P2
PKA
protein kinase A
transient receptor potential channel
TRP channel
TRPV Cation Channels - genetics
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Summary:Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca2+-selective ion channel that plays a key role in Ca2+ homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and inhibition by Ca2+-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca2+ 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)P2 activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P2 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. [Display omitted] •The TRPV5 ion channel is essential for calcium homeostasis•Acidic pH inhibits TRPV5 through conformational change and loss of PI(4,5)P2•PKA phosphorylates TRPV5 and prevents CaM inactivation Fluck et al. investigate how the activity of TRPV5 is decreased by acidic pH environments and increased by PKA phosphorylation. Combining cryo-EM and electrophysiology, their results show that acidic environments cause channel closing and loss of PI(4,5)P2 binding, whereas PKA phosphorylation disrupts CaM inactivation.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.110737