The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons
JournalFrontiers in Pharmacology
PublisherFrontiers Media S.A.
MetadataShow full item record
AbstractTransient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its binding sites in the pore region. We demonstrated that external protons block TRPM3 with an inhibitory pH50 of 5.5. whereas internal protons inhibit TRPM3 with an inhibitory pH50 of 6.9. We identified three titratable residues, D1059, D1062, and D1073, at the vestibule of the channel pore that contributes to pH sensitivity. The mutation of D1073Q reduced TRPM3 current by low external pH 5.5 from 62 ± 3% in wildtype to 25 ± 6.0% in D1073Q mutant. These results indicate that D1073 is essential for pH sensitivity. In addition, we found that a single mutation of D1059 or D1062 enhanced pH sensitivity. In summary, our findings identify molecular determinants respionsible for the pH regulation of TRPM3. The inhibition of TRPM3 by protons may indicate an endogenous mechanism governing TRPM3 gating and its physiological/pathological functions.
Rights/TermsCopyright © 2021 Hossain Saad, Xiang, Liao, Reznikov and Du.
transient receptor potential channels
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/14799
- Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity.
- Authors: Du J, Xie J, Yue L
- Issue date: 2009 Dec
- Structural requirements of steroidal agonists of transient receptor potential melastatin 3 (TRPM3) cation channels.
- Authors: Drews A, Mohr F, Rizun O, Wagner TF, Dembla S, Rudolph S, Lambert S, Konrad M, Philipp SE, Behrendt M, Marchais-Oberwinkler S, Covey DF, Oberwinkler J
- Issue date: 2014 Feb
- Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients.
- Authors: Cabanas H, Muraki K, Eaton N, Balinas C, Staines D, Marshall-Gradisnik S
- Issue date: 2018 Aug 14
- Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients.
- Authors: Cabanas H, Muraki K, Balinas C, Eaton-Fitch N, Staines D, Marshall-Gradisnik S
- Issue date: 2019 Apr 23
- Control of Insulin Release by Transient Receptor Potential Melastatin 3 (TRPM3) Ion Channels.
- Authors: Becker A, Mannebach S, Mathar I, Weissgerber P, Freichel M, Loodin AP, Fecher-Trost C, Belkacemi A, Beck A, Philipp SE
- Issue date: 2020 Nov 10