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A molecular determinant of phosphoinositide affinity in mammalian TRPV channels

Velisetty, P
; 
Borbiro, I
; 
Kasimova, MA
; 
Liu, L
; 
Badheka, D
; 
Carnevale, V
; 
Rohacs, T
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Journal Article
Date
2016-06-13
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Subject
Animals
 Calcium
 Calcium Channels
 Ciona intestinalis
 Computer Simulation
 HEK293 Cells
 Humans
 Lipids
 Molecular Conformation
 Molecular Docking Simulation
 Mutation
 Oocytes
 Patch-Clamp Techniques
 Phosphatidylinositols
 Phospholipases
 Protein Binding
 Protein Conformation
 TRPV Cation Channels
 Xenopus laevis
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http://hdl.handle.net/20.500.12613/4214
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A molecular determinant of phosphoinositide affinity in mammalian TRPV channels.pdf
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DOI
10.1038/srep27652
Abstract
Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 ] is an important cofactor for ion channels. Affinity for this lipid is a major determinant of channel inhibition by depletion of PI(4,5)P2 upon phospholipase C (PLC) activation. Little is known about what determines PI(4,5)P2 affinity in mammalian ion channels. Here we report that two members of the Transient Receptor Potential Vanilloid (TRPV) ion channel family, TRPV5 and TRPV6 lack a positively charged residue in the TM4-TM5 loop that was shown to interact with PI(4,5)P2 in TRPV1, which shows high affinity for this lipid. When this positively charged residue was introduced to either TRPV6 or TRPV5, they displayed markedly higher affinities for PI(4,5)P2, and were largely resistant to inhibition by PI(4,5)P2 depletion. Furthermore, Ca2+ -induced inactivation of TRPV6 was essentially eliminated in the G488R mutant, showing the importance of PLC-mediated PI(4,5)P2 depletion in this process. Computational modeling shows that the introduced positive charge interacts with PI(4,5)P2 in TRPV6.
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Springer Science and Business Media LLC
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Scientific Reports
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