Designer Genetically Encoded Voltage-dependent Calcium Channel Inhibitors Inspired by RGK GTPases

Overview

Journal J Physiol

Specialty Physiology

Date 2020 Feb 28

PMID 32104913

Citations 11

Authors

Henry M Colecraft

Affiliations

Soon will be listed here.

Abstract

High-voltage-activated calcium (Ca 1/Ca 2) channels translate action potentials into Ca influx in excitable cells to control essential biological processes that include; muscle contraction, synaptic transmission, hormone secretion and activity-dependent regulation of gene expression. Modulation of Ca 1/Ca 2 channel activity is a powerful mechanism to regulate physiology, and there are a host of intracellular signalling molecules that tune different aspects of Ca channel trafficking and gating for this purpose. Beyond normal physiological regulation, the diverse Ca channel modulatory mechanisms may potentially be co-opted or interfered with for therapeutic benefits. Ca 1/Ca 2 channels are potently inhibited by a four-member sub-family of Ras-like GTPases known as RGK (Rad, Rem, Rem2, Gem/Kir) proteins. Understanding the mechanisms by which RGK proteins inhibit Ca 1/Ca 2 channels has led to the development of novel genetically encoded Ca channel blockers with unique properties; including, chemo- and optogenetic control of channel activity, and blocking channels either on the basis of their subcellular localization or by targeting an auxiliary subunit. These genetically encoded Ca channel inhibitors have outstanding utility as enabling research tools and potential therapeutics.

Citing Articles

Electrically Active Biomaterials for Stimulation and Regeneration in Tissue Engineering.

Park J, Akbaba G, Sharma N, Das R, Vinikoor T, Liu Y J Biomed Mater Res A. 2025; 113(1):e37871.

PMID: 39806919 PMC: 11773453. DOI: 10.1002/jbm.a.37871.

Rad protein: An essential player in L-type Ca2+ channel localization and modulation in cardiomyocytes.

Kong C, Dries E J Gen Physiol. 2024; 156(10).

PMID: 39172109 PMC: 11344166. DOI: 10.1085/jgp.202413629.

Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.

Morgenstern T, Darko-Boateng A, Afriyie E, Shanmugam S, Zhou X, Choudhury P bioRxiv. 2024; .

PMID: 38854018 PMC: 11160594. DOI: 10.1101/2024.05.28.596281.

Exploring the memory: existing activity-dependent tools to tag and manipulate engram cells.

Pang B, Wu X, Chen H, Yan Y, Du Z, Yu Z Front Cell Neurosci. 2024; 17:1279032.

PMID: 38259503 PMC: 10800721. DOI: 10.3389/fncel.2023.1279032.

Design and Applications of Genetically-Encoded Voltage-Dependent Calcium Channel Inhibitors.

Gavin A, Colecraft H Handb Exp Pharmacol. 2023; 279:139-155.

PMID: 37306815 DOI: 10.1007/164_2023_656.

References

Dolphin A . Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nat Rev Neurosci. 2012; 13(8):542-55. DOI: 10.1038/nrn3311. View

Liu G, Papa A, Katchman A, Zakharov S, Roybal D, Hennessey J . Mechanism of adrenergic Ca1.2 stimulation revealed by proximity proteomics. Nature. 2020; 577(7792):695-700. PMC: 7018383. DOI: 10.1038/s41586-020-1947-z. View

Berridge M, Lipp P, Bootman M . The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2001; 1(1):11-21. DOI: 10.1038/35036035. View

Meissner M, Weissgerber P, Camacho Londono J, Prenen J, Link S, Ruppenthal S . Moderate calcium channel dysfunction in adult mice with inducible cardiomyocyte-specific excision of the cacnb2 gene. J Biol Chem. 2011; 286(18):15875-82. PMC: 3091197. DOI: 10.1074/jbc.M111.227819. View

Makarewich C, Correll R, Gao H, Zhang H, Yang B, Berretta R . A caveolae-targeted L-type Ca²+ channel antagonist inhibits hypertrophic signaling without reducing cardiac contractility. Circ Res. 2012; 110(5):669-74. PMC: 3324037. DOI: 10.1161/CIRCRESAHA.111.264028. View

Kim E, Rumpf C, Fujiwara Y, Cooley E, Van Petegem F, Minor Jr D . Structures of CaV2 Ca2+/CaM-IQ domain complexes reveal binding modes that underlie calcium-dependent inactivation and facilitation. Structure. 2008; 16(10):1455-67. PMC: 2701236. DOI: 10.1016/j.str.2008.07.010. View

Chen Y, Li M, Zhang Y, He L, Yamada Y, Fitzmaurice A . Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature. 2004; 429(6992):675-80. DOI: 10.1038/nature02641. View

Dolphin A . G protein modulation of voltage-gated calcium channels. Pharmacol Rev. 2003; 55(4):607-27. DOI: 10.1124/pr.55.4.3. View

Adams P, Ben-Johny M, Dick I, Inoue T, Yue D . Apocalmodulin itself promotes ion channel opening and Ca(2+) regulation. Cell. 2014; 159(3):608-22. PMC: 4349394. DOI: 10.1016/j.cell.2014.09.047. View

10.

Yang T, Xu X, Kernan T, Wu V, Colecraft H . Rem, a member of the RGK GTPases, inhibits recombinant CaV1.2 channels using multiple mechanisms that require distinct conformations of the GTPase. J Physiol. 2010; 588(Pt 10):1665-81. PMC: 2887986. DOI: 10.1113/jphysiol.2010.187203. View

11.

Finlin B, Andres D . Rem is a new member of the Rad- and Gem/Kir Ras-related GTP-binding protein family repressed by lipopolysaccharide stimulation. J Biol Chem. 1997; 272(35):21982-8. DOI: 10.1074/jbc.272.35.21982. View

12.

Li Y, Wu Y, Zhou Y . Modulation of inactivation properties of CaV2.2 channels by 14-3-3 proteins. Neuron. 2006; 51(6):755-71. DOI: 10.1016/j.neuron.2006.08.014. View

13.

Yang T, Colecraft H . Regulation of voltage-dependent calcium channels by RGK proteins. Biochim Biophys Acta. 2012; 1828(7):1644-54. PMC: 4190112. DOI: 10.1016/j.bbamem.2012.10.005. View

14.

Wang G, Zhu X, Xie W, Han P, Li K, Sun Z . Rad as a novel regulator of excitation-contraction coupling and beta-adrenergic signaling in heart. Circ Res. 2009; 106(2):317-27. DOI: 10.1161/CIRCRESAHA.109.208272. View

15.

Zamponi G, Striessnig J, Koschak A, Dolphin A . The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol Rev. 2015; 67(4):821-70. PMC: 4630564. DOI: 10.1124/pr.114.009654. View

16.

Dick I, Tadross M, Liang H, Tay L, Yang W, Yue D . A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature. 2008; 451(7180):830-4. PMC: 4262256. DOI: 10.1038/nature06529. View

17.

Ma G, Liu J, Ke Y, Liu X, Li M, Wang F . Optogenetic Control of Voltage-Gated Calcium Channels. Angew Chem Int Ed Engl. 2018; 57(24):7019-7022. PMC: 6032918. DOI: 10.1002/anie.201713080. View

18.

Finlin B, Crump S, Satin J, Andres D . Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases. Proc Natl Acad Sci U S A. 2003; 100(24):14469-74. PMC: 283615. DOI: 10.1073/pnas.2437756100. View

19.

Erickson M, Alseikhan B, Peterson B, Yue D . Preassociation of calmodulin with voltage-gated Ca(2+) channels revealed by FRET in single living cells. Neuron. 2001; 31(6):973-85. DOI: 10.1016/s0896-6273(01)00438-x. View

20.

Peterson B, DeMaria C, Adelman J, Yue D . Calmodulin is the Ca2+ sensor for Ca2+ -dependent inactivation of L-type calcium channels. Neuron. 1999; 22(3):549-58. DOI: 10.1016/s0896-6273(00)80709-6. View