Regulation of ThermoTRP Channels by PIP2 and Cholesterol

Rosenbaum, Tamara; Morales‐Lázaro, Sara L.

doi:10.1007/978-3-031-21547-6_9

“…The main differences between the seven TRP channel subfamilies are found in the N-and C-terminal cytosolic domains, which contain putative protein inter-action and regulatory motifs [40]. TRP channels are activated in several ways: directly by endogenous agents, including diacylglycerols [41], phosphoinositides [42], eicosanoids [43], anandamide [44], and reactive oxygen species (ROS) and their byproducts [45,46], and by an unprecedented series of exogenous compounds, such as capsaicin [47], icilin [48], allicin [49], allyl isothiocyanate (AITC) [50,51], isopetasin [52], umbellulone [53,54], parthenolide [55], and acrolein [56], or indirectly, by intracellular mediators produced by the activation of G protein-coupled receptor (GPCR) or tyrosine kinases receptor [57].…”

Section: Trp Channelsmentioning

confidence: 99%

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

Marini,

Titiz,

Souza Monteiro de Araújo

et al. 2023

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Ion channels play a crucial role in a wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family of channels has emerged as a promising therapeutic target due to its involvement in several stages of cancer development and dissemination. TRP channels are expressed in a large variety of cells and tissues, and by increasing cation intracellular concentration, they monitor mechanical, thermal, and chemical stimuli under physiological and pathological conditions. Some members of the TRP superfamily, namely vanilloid (TRPV), canonical (TRPC), melastatin (TRPM), and ankyrin (TRPA), have been investigated in different types of cancer, including breast, prostate, lung, and colorectal cancer. TRP channels are involved in processes such as cell proliferation, migration, invasion, angiogenesis, and drug resistance, all related to cancer progression. Some TRP channels have been mechanistically associated with the signaling of cancer pain. Understanding the cellular and molecular mechanisms by which TRP channels influence cancer provides new opportunities for the development of targeted therapeutic strategies. Selective inhibitors of TRP channels are under initial scrutiny in experimental animals as potential anti-cancer agents. In-depth knowledge of these channels and their regulatory mechanisms may lead to new therapeutic strategies for cancer treatment, providing new perspectives for the development of effective targeted therapies.

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PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

Clarke,

Skerjanz,

Gsell

et al. 2024

Nat Commun

2

0

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The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP2. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP2 predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP2 sensing involves a multistep mechanism that propagates from L3 to the pore domain via a salt bridge between the TRP helix and S4-S5 linker. Notably, we find that both stimulated and constitutive TRPC3 activity require PIP2. These structural insights into the function of TRPC3 are invaluable for understanding the role of the TRPC subfamily in health and disease, in particular for cardiovascular diseases, in which TRPC3 channels play a major role.

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Coordinating the regulatory dance: how PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

Clarke,

Skerjanz,

Gsell

et al. 2023

Preprint

0

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The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP2. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP2 predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP2 sensing involves a multistep mechanism that propagates from L3 to the pore domain via a salt bridge between the TRP helix and S4-S5 linker. Notably, we find that both stimulated and constitutive TRPC3 activity require PIP2. These structural insights into the function of TRPC3 are invaluable for understanding the role of the TRPC subfamily in health and disease in native tissue.

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Regulation of ThermoTRP Channels by PIP2 and Cholesterol

Cited by 4 publications

References 162 publications

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

Coordinating the regulatory dance: how PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

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