GSK1702934A and M085 directly activate TRPC6 via a mechanism of stimulating the extracellular cavity formed by the pore helix and transmembrane helix S6

Yang, Ping-Feng; Li, Xinghua; Wang, Jin; Ma, Xuefei; Zhou, Bo-Ying; Jiao, Yuan-Feng; Wang, Wenhui; Cao, Peng; Zhu, Michael X.; Li, Pei-Wang; Xiao, Zhihong; Li, Changzhu; Guo, Chengjun; Lei, Yuntao; Yu, Ye

doi:10.1016/j.jbc.2021.101125

Cited by 10 publications

(12 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The estimation of binding energy by docking scoring functions showed that compound C20 and AM-0883 had similar values (−9.2 and −9.7 kcal/mol, respectively). Thus, we conclude that C20 activates TRPC6 via the same molecular mechanism of stimulating the extracellular site formed by the pore helix and transmembrane helix S6 [ 17 , 18 ] as formerly reported agonists of TRPC6.…”

Section: Resultsmentioning

confidence: 66%

“…The first complex of TRPC6 with the agonist AM-0883 was published in 2020 [ 17 ]. In the following year two structures with other TRPC6 positive modulators, GSK1702934A and M085, were solved [ 18 ]. They demonstrated that three different chemical structures of TRPC6 positive regulators (AM-0883, GSK1702934A and M085), activate TRPC6 via interaction with the extracellular site formed by the pore helix and transmembrane helix S6 [ 17 , 18 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

Zernov

Veselovsky

Poroikov

et al. 2022

IJMS

View full text Add to dashboard Cite

Synapse loss in the brain of Alzheimer’s disease patients correlates with cognitive dysfunctions. Drugs that limit synaptic loss are promising pharmacological agents. The transient receptor potential cation channel, subfamily C, member 6 (TRPC6) regulates the formation of an excitatory synapse. Positive regulation of TRPC6 results in increased synapse formation and enhances learning and memory in animal models. The novel selective TRPC6 agonist, 3-(3-,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one, has recently been identified. Here we present in silico, in vitro, ex vivo, pharmacokinetic and in vivo studies of this compound. We demonstrate that it binds to the extracellular agonist binding site of the human TRPC6, protects hippocampal mushroom spines from amyloid toxicity in vitro, efficiently recovers synaptic plasticity in 5xFAD brain slices, penetrates the blood–brain barrier and recovers cognitive deficits in 5xFAD mice. We suggest that C20 might be recognized as the novel TRPC6-selective drug suitable to treat synaptic deficiency in Alzheimer’s disease-affected hippocampal neurons.

show abstract

Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

Zernov

Veselovsky

Poroikov

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…To assess whether 2-LG activates mammalian TRPC channels, we used Fura-2 to evaluate the Ca 2+ responses of human embryonic kidney (HEK) 293 cells transiently expressing mouse TRPC5 or TRPC6. We exposed the cells to 2-LG, then to either riluzole or GSK1702934A, which are nonlipid activators of TRPC5 and TRPC6, respectively ( 47 , 48 ), and lastly with ionomycin. 2-LG induced significant Ca 2+ increases in TRPC5- and TRPC6-expressing HEK293 cells compared with the vector-transfected cells, although the responsiveness varied among the cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endocannabinoids produced in photoreceptor cells in response to light activate Drosophila TRP channels

et al. 2022

View full text Add to dashboard Cite

Drosophila phototransduction is a model for signaling cascades that culminate in the activation of transient receptor potential (TRP) cation channels. TRP and TRPL are the canonical TRP (TRPC) channels that are regulated by light stimulation of rhodopsin and engagement of Gα q and phospholipase Cβ (PLC). Lipid metabolite(s) generated downstream of PLC are essential for the activation of the TRPC channels in photoreceptor cells. We sought to identify the key lipids produced subsequent to PLC stimulation that contribute to channel activation. Here, using genetics, lipid analysis, and Ca 2+ imaging, we found that light increased the amount of an abundant endocannabinoid, 2-linoleoyl glycerol (2-LG), in vivo. The increase in 2-LG amounts depended on the PLC and diacylglycerol lipase encoded by norpA and inaE , respectively. This endocannabinoid facilitated TRPC-dependent Ca 2+ influx in a heterologous expression system and in dissociated ommatidia from compound eyes. Moreover, 2-LG and mechanical stimulation cooperatively activated TRPC channels in ommatidia. We propose that 2-LG is a physiologically relevant endocannabinoid that activates TRPC channels in photoreceptor cells.

show abstract

“…As previously described ( Laio et al, 2005 ; Limongelli et al, 2010 ; Zhao et al, 2014 ; Wang et al, 2018 ; Yang et al, 2021 ), all metadynamics simulations were performed by DESMOND under NPT and periodic boundary conditions using the default parameters at constant temperature (300 K) and pressure (1 bar). The distances between the key residue of MOR and the ligand (morphine and naloxone) were set to CVs.…”

Section: Methodsmentioning

confidence: 99%

Dynamic recognition of naloxone, morphine and endomorphin1 in the same pocket of µ-opioid receptors

Zhang

Sun

Zhang

et al. 2022

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

Morphine, the most widely used analgesic, relieves severe pain by activating the μ-opioid receptor (MOR), whereas naloxone, with only slight structural changes compared to morphine, exhibits inhibitory effect, and is used to treat opioid abuse. The mechanism by which the MOR distinguishes between the two is unclear. Molecular dynamics (MD) simulations on a 1-μs time scale and metadynamics-enhanced conformational sampling are used here to determine the different interactions of these two ligands with MOR: morphine adjusted its pose by continuously flipping deeper into the pocket, whereas naloxone failed to penetrate deeper because its allyl group conflicts with several residues of MOR. The endogenous peptide ligand endomorphin-1 (EM-1) underwent almost no significant conformational changes during the MD simulations. To validate these processes, we employed GIRK4S143T, a MOR-activated Gβγ-protein effector, in combination with mutagenesis and electrophysiological recordings. We verified the role of some key residues in the dynamic recognition of naloxone and morphine and identified the key residue I322, which leads to differential recognition of morphine and naloxone while assisting EM-1 in activating MOR. Reducing the side chain size of I322 (MORI322A) transformed naloxone from an inhibitor directly into an agonist of MOR, and I322A also significantly attenuated the potency of MOR on EM-1, confirming that binding deep in the pocket is critical for the agonistic effect of MOR. This finding reveals a dynamic mechanism for the response of MOR to different ligands and provides a basis for the discovery of new ligands for MOR at the atomic level.

show abstract

GSK1702934A and M085 directly activate TRPC6 via a mechanism of stimulating the extracellular cavity formed by the pore helix and transmembrane helix S6

Cited by 10 publications

References 60 publications

New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

Endocannabinoids produced in photoreceptor cells in response to light activate Drosophila TRP channels

Dynamic recognition of naloxone, morphine and endomorphin1 in the same pocket of µ-opioid receptors

Contact Info

Product

Resources

About