ArticleThe Journal of physiology2010
Rem, a member of the RGK GTPases, inhibits recombinant CaV1.2 channels using multiple mechanisms that require distinct conformations of the GTPase.
Article in The Journal of physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 79 citations in OpenAlex.
- A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings.Science advances · 2024Article
- The C-terminus of Rad is required for membrane localization and L-type calcium channel regulation.The Journal of general physiology · 2024Article
- The interplay of inflammation, exosomes and CaCardiovascular diabetology · 2023Review
- Inactivation influences the extent of inhibition of voltage-gated CaFrontiers in physiology · 2023Article
- Design and Applications of Genetically-Encoded Voltage-Dependent Calcium Channel Inhibitors.Handbook of experimental pharmacology · 2023Review
- Selective posttranslational inhibition of CaNature communications · 2022Article
- Calcium current modulation by the γ1 subunit depends on alternative splicing of CaV1.1.The Journal of general physiology · 2022Article
- Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances.International journal of molecular sciences · 2021Review
- Into the spotlight: RGK proteins in skeletal muscle.Cell calcium · 2021Review
- The life cycle of voltage-gated CaNeuronal signaling · 2021Review
- Tissue-specific adrenergic regulation of the L-type CaScience signaling · 2020Review
- Regulation of cardiovascular calcium channel activity by post-translational modifications or interacting proteins.Pflugers Archiv : European journal of physiology · 2020Review
- Designer genetically encoded voltage-dependent calcium channel inhibitors inspired by RGK GTPases.The Journal of physiology · 2020Review
- Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action andThe Journal of biological chemistry · 2020Article
- α-Actinin-1 promotes activity of the L-type CaThe EMBO journal · 2020Article
- A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary CaeLife · 2019Article
- Engineering selectivity into RGK GTPase inhibition of voltage-dependent calcium channels.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Differentiation, Maintenance, and Analysis of Human Retinal Pigment Epithelium Cells: A Disease-in-a-dish Model for BEST1 Mutations.Journal of visualized experiments : JoVE · 2018Article
- Duplex signaling by CaM and Stac3 enhances CaThe Journal of general physiology · 2018Article
- Expression and Purification of Mammalian Bestrophin Ion Channels.Journal of visualized experiments : JoVE · 2018Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
Rad/Rem/Gem/Kir (RGK) GTPases potently inhibit Ca(V)1 and Ca(V)2 (Ca(V)1-2) channels, a paradigm of ion channel regulation by monomeric G-proteins with significant physiological ramifications and potential biotechnology applications. The mechanism(s) underlying how RGK proteins inhibit I(Ca) is unknown, and it is unclear how key structural and regulatory properties of these GTPases (such as the role of GTP binding to the nucleotide binding domain (NBD), and the C-terminus which contains a membrane-targeting motif) feature in this effect. Here, we show that Rem inhibits Ca(V)1.2 channels by three independent mechanisms that rely on distinct configurations of the GTPase: (1) a reduction in surface density of channels is accomplished by enhancing dynamin-dependent endocytosis, (2) a diminution of channel open probability (P(o)) that occurs without impacting on voltage sensor movement, and (3) an immobilization of Ca(V) channel voltage sensors. The presence of both the Rem NBD and C-terminus (whether membrane-targeted or not) in one molecule is sufficient to reconstitute all three mechanisms. However, membrane localization of the NBD by a generic membrane-targeting module reconstitutes only the decreased P(o) function (mechanism 2). A point mutation that prevents GTP binding to the NBD selectively eliminates the capacity to immobilize voltage sensors (mechanism 3). The results reveal an uncommon multiplicity in the mechanisms Rem uses to inhibit I(Ca), predict new physiological dimensions of the RGK GTPase-Ca(V) channel crosstalk, and suggest original approaches for developing novel Ca(V) channel blockers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.