Molecular architecture of the Gαi-bound TRPC5 ion channel

Won, Jongdae; Kim, Jinsung; Jeong, Hyomin; Kim, Jinhyeong; Feng, Shasha; Jeong, Byeongseok; Kwak, Misun; Ko, Jung Hwa; Im, Wonpil; So, Insuk; Lee, Hyung Ho

doi:10.1038/s41467-023-38281-3

Cited by 13 publications

(9 citation statements)

References 90 publications

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“…The ability to observe different types of water molecules in membranes and the feasibility of differentiation of the environment in ion channels by 17 O NMR experiments are unique and exciting. The use of nanodiscs to measure residual 17 O quadrupole couplings to study the structure and dynamics of membrane-bound water and to study the phase transition of encased lipids opens new avenues in membrane biophysics. − The fact that water plays a crucial role in biology and the advent of higher magnetic fields and better NMR instrumentations renders more sophisticated NMR techniques, the benefits of 17 O based NMR applications can be expected to grow remarkably. Therefore, we conclude that much remains to be done to fully utilize the power of 17 O based NMR spectroscopy to study biological solids.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes

Fu,

Ramamoorthy

2024

J. Phys. Chem. B

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Despite the limitations posed by poor sensitivity, studies have reported the unique advantages of 17 O based NMR spectroscopy to study systems existing in liquid, solid, or semisolid states. 17 O NMR studies have exploited the remarkable sensitivity of quadrupole coupling and chemical shift anisotropy tensors to the local environment in the characterization of a variety of intraand intermolecular interactions and motion. Recent studies have considerably expanded the use of 17 O NMR to study dynamic intermolecular interactions associated with some of the challenging biological systems under magic angle spinning (MAS) and aligned conditions. The very fast relaxing nature of 17 O has been well utilized in cellular and in vivo MRS (magnetic resonance spectroscopy) and MRI (magnetic resonance imaging) applications. The main focus of this Review is to highlight the new developments in the biological solids with a detailed discussion for a few selected examples including membrane proteins and nanodiscs. In addition to the unique benefits and limitations, the remaining challenges to overcome, and the impacts of higher magnetic fields and sensitivity enhancement techniques are discussed.

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Section: Summary and Future Directionsmentioning

confidence: 99%

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes

Fu,

Ramamoorthy

2024

J. Phys. Chem. B

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“…There is a possibility that ion channels and GPCRs may coexist in close proximity, forming a signaling cluster within a specific region of the plasma membrane ( Neves et al, 2002 ). The recent cryo-EM structure demonstrated that Gα i3 could directly activate the TRPC5 channels, and the channel requires both Ca 2+ and PIP 2 as essential cofactors for the complete activation of Gα i3 ( Won et al, 2023 ).…”

Section: Two Major Kinds Of G Protein: Small G Protein and Heterotrim...mentioning

confidence: 99%

“…Initial studies suggested that the binding sites for G protein exist at the rib helix of TRPC4/5 channels or the CIRB domain ( Jeon et al, 2012 ). However, recent cryo-EM structure showed that IYY 58-60 amino acids at ARD bind with G i3 protein ( Won et al, 2023 ). Main debate concerns with the role of PIP 2 .…”

Section: Trpc4/5 Activation Mechanism: Pip 2 Ca ...mentioning

confidence: 99%

“…Moreover, several features in intracellular regions of TRPC channels are conserved: the pre-S1 elbow is situated in the N-terminal domain, and the connecting helix runs parallel to the membrane bilayer. However, the binding interface with Gα i protein was conserved only in the N-terminal ankyrin repeat domain (ARD) of TRPC4 and TRPC5 channels, which means both channels may be the only direct modulators for Gα proteins in TRP subfamily ( Won et al, 2023 ). The binding interface of Gα protein with its effector molecules was also found to be conserved in the Gα i -bound TRPC5 cryo-EM structure ( Lyon et al, 2013 ; Won et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, the binding interface with Gα i protein was conserved only in the N-terminal ankyrin repeat domain (ARD) of TRPC4 and TRPC5 channels, which means both channels may be the only direct modulators for Gα proteins in TRP subfamily ( Won et al, 2023 ). The binding interface of Gα protein with its effector molecules was also found to be conserved in the Gα i -bound TRPC5 cryo-EM structure ( Lyon et al, 2013 ; Won et al, 2023 ). In conjunction with the electrophysiological result demonstrating that Gα i3 increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP 2 ), this structural discovery provides evidence that ion channel activity can be directly regulated by Gα protein following GPCR activation.…”

Section: Introductionmentioning

confidence: 99%

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Direct modulation of TRPC ion channels by Gα proteins

Kang,

Kim,

Park

et al. 2024

Front. Physiol.

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GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP2 and releases DAG and IP3. This IP3 increases intracellular Ca2+ and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-Gi/o protein antibodies in GI smooth muscle, indicating the involvement of Gαi/o protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active GαiQL proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by Gi/o proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY58-60 amino acids at ARD of TRPC5 binds with Gi3 protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for Gi and Gq pathway as Gq pathway increases intracellular Ca2+ and the increased Ca2+ facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (IM) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-Gi protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.

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Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel

Ptakova,

Zimova,

Barvik

et al. 2024

Cell. Mol. Life Sci.

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Lysophosphatidylcholine (LPC) is a bioactive lipid present at high concentrations in inflamed and injured tissues where it contributes to the initiation and maintenance of pain. One of its important molecular effectors is the transient receptor potential canonical 5 (TRPC5), but the explicit mechanism of the activation is unknown. Using electrophysiology, mutagenesis and molecular dynamics simulations, we show that LPC-induced activation of TRPC5 is modulated by xanthine ligands and depolarizing voltage, and involves conserved residues within the lateral fenestration of the pore domain. Replacement of W577 with alanine (W577A) rendered the channel insensitive to strong depolarizing voltage, but LPC still activated this mutant at highly depolarizing potentials. Substitution of G606 located directly opposite position 577 with tryptophan rescued the sensitivity of W577A to depolarization. Molecular simulations showed that depolarization widens the lower gate of the channel and this conformational change is prevented by the W577A mutation or removal of resident lipids. We propose a gating scheme in which depolarizing voltage and lipid-pore helix interactions act together to promote TRPC5 channel opening.

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Molecular architecture of the Gαi-bound TRPC5 ion channel

Cited by 13 publications

References 90 publications

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes

Direct modulation of TRPC ion channels by Gα proteins

Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel

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Molecular architecture of the Gαi-bound TRPC5 ion channel

Cited by 13 publications

References 90 publications

17O Solid-State NMR Spectroscopy of Lipid Membranes

17O Solid-State NMR Spectroscopy of Lipid Membranes

Direct modulation of TRPC ion channels by Gα proteins

Functional determinants of lysophospholipid- and voltage-dependent regulation of TRPC5 channel

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Product

Resources

About

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes

¹⁷O Solid-State NMR Spectroscopy of Lipid Membranes