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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Review Article

Advances in L-Type Calcium Channel Structures, Functions and Molecular Modeling

Author(s): Lei Xu*, Lilei Sun, Liangxu Xie, Shanzhi Mou, Dawei Zhang, Jingyu Zhu and Peng Xu*

Volume 28, Issue 3, 2021

Published on: 14 July, 2020

Page: [514 - 524] Pages: 11

DOI: 10.2174/0929867327666200714154059

Price: $65

Abstract

L-type Calcium Channels (LTCCs), also termed as Cav1, belong to voltage-gated calcium channels (VGCCs/Cavs), which play a critical role in a wide spectrum of physiological processes, including neurotransmission, cell cycle, muscular contraction, cardiac action potential and gene expression. Aberrant regulation of calcium channels is involved in neurological, cardiovascular, muscular and psychiatric disorders. Accordingly, LTCCs have been regarded as important drug targets, and a number of LTCC drugs are in clinical use. In this review, the recent development of structures and biological functions of LTCCs are introduced. Moreover, the representative modulators and ligand binding sites of LTCCs are discussed. Finally, molecular modeling and Computer-aided Drug Design (CADD) methods for understanding structure-function relations of LTCCs are summarized.

Keywords: L-type calcium channels, voltage-gated calcium channels, isoform-selective VGCC modulators, drugbindingsites, computer-aided drug design, molecular modeling.

« Previous Next »
[1]
Zamponi, G.W. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat. Rev. Drug Discov., 2016, 15(1), 19-34.
[http://dx.doi.org/10.1038/nrd.2015.5] [PMID: 26542451]
[2]
Catterall, W.A. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol., 2011, 3(8)a003947
[http://dx.doi.org/10.1101/cshperspect.a003947] [PMID: 21746798]
[3]
Bourinet, E.; Zamponi, G.W. Block of voltage-gated calcium channels by peptide toxins. Neuropharmacology, 2017, 127, 109-115.
[http://dx.doi.org/10.1016/j.neuropharm.2016.10.016] [PMID: 27756538]
[4]
Simms, B.A.; Zamponi, G.W. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron, 2014, 82(1), 24-45.
[http://dx.doi.org/10.1016/j.neuron.2014.03.016] [PMID: 24698266]
[5]
Vega-Vela, N.E.; Osorio, D.; Avila-Rodriguez, M.; Gonzalez, J.; García-Segura, L.M.; Echeverria, V.; Barreto, G.E. L-type calcium channels modulation by estradiol. Mol. Neurobiol., 2017, 54(7), 4996-5007.
[http://dx.doi.org/10.1007/s12035-016-0045-6] [PMID: 27525676]
[6]
Tang, L.; El-Din, T.M.G.; Payandeh, J.; Martinez, G.Q.; Heard, T.M.; Scheuer, T.; Zheng, N.; Catterall, W.A. Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature, 2014, 505(7481), 56-61.
[http://dx.doi.org/10.1038/nature12775] [PMID: 24270805]
[7]
Tang, L.; El-Din, T.M.G.; Swanson, T.M.; Pryde, D.C.; Scheuer, T.; Zheng, N.; Catterall, W.A. Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature, 2016, 537(7618), 117-121.
[http://dx.doi.org/10.1038/nature19102] [PMID: 27556947]
[8]
Wu, J.; Yan, Z.; Li, Z.; Yan, C.; Lu, S.; Dong, M.; Yan, N. Structure of the voltage-gated calcium channel Cav1.1 complex. Science, 2015, 350(6267)aad2395
[http://dx.doi.org/10.1126/science.aad2395] [PMID: 26680202]
[9]
Wu, J.; Yan, Z.; Li, Z.; Qian, X.; Lu, S.; Dong, M.; Zhou, Q.; Yan, N. Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature, 2016, 537(7619), 191-196.
[http://dx.doi.org/10.1038/nature19321] [PMID: 27580036]
[10]
Zhao, Y.; Huang, G.; Wu, J.; Wu, Q.; Gao, S.; Yan, Z.; Lei, J.; Yan, N. Molecular basis for ligand modulation of a mammalian voltage-gated Ca2+ channel. Cell, 2019, 177(6), 1495.e12-1506.e12.
[http://dx.doi.org/10.1016/j.cell.2019.04.043] [PMID: 31150622]
[11]
Catterall, W.A.; Perez-Reyes, E.; Snutch, T.P.; Striessnig, J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev., 2005, 57(4), 411-425.
[http://dx.doi.org/10.1124/pr.57.4.5] [PMID: 16382099]
[12]
Shimomura, T.; Yonekawa, Y.; Nagura, H.; Tateyama, M.; Fujiyoshi, Y.; Irie, K. A native prokaryotic voltage-dependent calcium channel with a novel selectivity filter sequence. eLife, 2020, 9e52828
[http://dx.doi.org/10.7554/eLife.52828] [PMID: 32093827]
[13]
Striessnig, J.; Pinggera, A.; Kaur, G.; Bock, G.; Tuluc, P. L-type Ca2+ channels in heart and brain. Wiley Interdiscip. Rev. Membr. Transp. Signal., 2014, 3(2), 15-38.
[http://dx.doi.org/10.1002/wmts.102] [PMID: 24683526]
[14]
Vargas, E.; Yarov-Yarovoy, V.; Khalili-Araghi, F.; Catterall, W.A.; Klein, M.L.; Tarek, M.; Lindahl, E.; Schulten, K.; Perozo, E.; Bezanilla, F.; Roux, B. An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J. Gen. Physiol., 2012, 140(6), 587-594.
[http://dx.doi.org/10.1085/jgp.201210873] [PMID: 23183694]
[15]
Hering, S.; Zangerl-Plessl, E-M.; Beyl, S.; Hohaus, A.; Andranovits, S.; Timin, E.N. Calcium channel gating. Pflugers Arch., 2018, 470(9), 1291-1309.
[http://dx.doi.org/10.1007/s00424-018-2163-7] [PMID: 29951751]
[16]
Catterall, W.A.; Lenaeus, M.J.; El-Din, T.M.G. Structure and pharmacology of voltage-gated sodium and calcium channels. Annu. Rev. Pharmacol. Toxicol., 2020, 60, 133-154.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021757] [PMID: 31537174]
[17]
Ferreira, G.; Yi, J.; Ríos, E.; Shirokov, R. Ion-dependent inactivation of barium current through L-type calcium channels. J. Gen. Physiol., 1997, 109(4), 449-461.
[http://dx.doi.org/10.1085/jgp.109.4.449] [PMID: 9101404]
[18]
Jurkat-Rott, K.; Lehmann-Horn, F. Paroxysmal muscle weakness: the familial periodic paralyses. J. Neurol., 2006, 253(11), 1391-1398.
[http://dx.doi.org/10.1007/s00415-006-0339-0] [PMID: 17139526]
[19]
Robinson, R.; Carpenter, D.; Shaw, M.A.; Halsall, J.; Hopkins, P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum. Mutat., 2006, 27(10), 977-989.
[http://dx.doi.org/10.1002/humu.20356] [PMID: 16917943]
[20]
Ortner, N.J.; Striessnig, J. L-type calcium channels as drug targets in CNS disorders. Channels (Austin), 2016, 10(1), 7-13.
[http://dx.doi.org/10.1080/19336950.2015.1048936] [PMID: 26039257]
[21]
Lee, S. Pharmacological inhibition of voltage-gated Ca(2+) channels for chronic pain relief. Curr. Neuropharmacol., 2013, 11(6), 606-620.
[http://dx.doi.org/10.2174/1570159X11311060005] [PMID: 24396337]
[22]
Godfraind, T. Discovery and development of calcium channel blockers. Front. Pharmacol., 2017, 8, 286.
[http://dx.doi.org/10.3389/fphar.2017.00286] [PMID: 28611661]
[23]
Striessnig, J.; Ortner, N.J.; Pinggera, A. Pharmacology of L-type calcium channels: novel drugs for old targets? Curr. Mol. Pharmacol., 2015, 8(2), 110-122.
[http://dx.doi.org/10.2174/1874467208666150507105845] [PMID: 25966690]
[24]
Carosati, E.; Ioan, P.; Micucci, M.; Broccatelli, F.; Cruciani, G.; Zhorov, B.S.; Chiarini, A.; Budriesi, R. 1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 2): action in other targets and antitargets. Curr. Med. Chem., 2012, 19(25), 4306-4323.
[http://dx.doi.org/10.2174/092986712802884204] [PMID: 22709009]
[25]
Edraki, N.; Mehdipour, A.R.; Khoshneviszadeh, M.; Miri, R. Dihydropyridines: evaluation of their current and future pharmacological applications. Drug Discov. Today, 2009, 14(21-22), 1058-1066.
[http://dx.doi.org/10.1016/j.drudis.2009.08.004] [PMID: 19729074]
[26]
Koschak, A.; Reimer, D.; Huber, I.; Grabner, M.; Glossmann, H.; Engel, J.; Striessnig, J. Alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J. Biol. Chem., 2001, 276(25), 22100-22106.
[http://dx.doi.org/10.1074/jbc.M101469200] [PMID: 11285265]
[27]
Kang, S.; Cooper, G.; Dunne, S.F.; Dusel, B.; Luan, C.H.; Surmeier, D.J.; Silverman, R.B. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease. Nat. Commun., 2012, 3(1), 1146.
[http://dx.doi.org/10.1038/ncomms2149] [PMID: 23093183]
[28]
Kang, S.; Cooper, G.; Dunne, S.F.; Luan, C.H.; James Surmeier, D.; Silverman, R.B. Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics. Bioorg. Med. Chem., 2013, 21(14), 4365-4373.
[http://dx.doi.org/10.1016/j.bmc.2013.04.054] [PMID: 23688558]
[29]
Franckowiak, G.; Bechem, M.; Schramm, M.; Thomas, G. The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels. Eur. J. Pharmacol., 1985, 114(2), 223-226.
[http://dx.doi.org/10.1016/0014-2999(85)90631-4] [PMID: 2412855]
[30]
Vo, D.; Wolowyk, M.W.; Knaus, E.E. Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des. Discov., 1992, 9(1), 69-78.
[PMID: 1360842]
[31]
Goldmann, S.; Stoltefuss, J. 1,4-dihydropyridines: effects of chirality and conformation on the calcium antagonist and calcium agonist activities. Angew. Chem. Int. Ed. Engl., 1991, 30(12), 1559-1578.
[http://dx.doi.org/10.1002/anie.199115591]
[32]
Tang, L.; El-Din, T.M.G.; Lenaeus, M.J.; Zheng, N.; Catterall, W.A. Structural basis for diltiazem block of a voltage-gated Ca2+ channel. Mol. Pharmacol., 2019, 96(4), 485-492.
[http://dx.doi.org/10.1124/mol.119.117531] [PMID: 31391290]
[33]
Srinivasan, V.; Sivaramakrishnan, H.; Karthikeyan, B. Detection, isolation and characterization of principal synthetic route indicative impurities in verapamil hydrochloride. Sci. Pharm., 2011, 79(3), 555-568.
[http://dx.doi.org/10.3797/scipharm.1101-19] [PMID: 21886903]
[34]
Li, W.; Shi, G. How CaV1.2-bound verapamil blocks Ca2+ influx into cardiomyocyte: atomic level views. Pharmacol. Res., 2019, 139, 153-157.
[http://dx.doi.org/10.1016/j.phrs.2018.11.017] [PMID: 30447294]
[35]
Musgaard, M.; Paramo, T.; Domicevica, L.; Andersen, O.J.; Biggin, P.C. Insights into channel dysfunction from modelling and molecular dynamics simulations. Neuropharmacology, 2018, 132, 20-30.
[http://dx.doi.org/10.1016/j.neuropharm.2017.06.030] [PMID: 28669899]
[36]
Doyle, D.A.; Morais Cabral, J.; Pfuetzner, R.A.; Kuo, A.; Gulbis, J.M.; Cohen, S.L.; Chait, B.T.; MacKinnon, R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science, 1998, 280(5360), 69-77.
[http://dx.doi.org/10.1126/science.280.5360.69] [PMID: 9525859]
[37]
Zhorov, B.S.; Folkman, E.V.; Ananthanarayanan, V.S. Homology model of dihydropyridine receptor: implications for L-type Ca(2+) channel modulation by agonists and antagonists. Arch. Biochem. Biophys., 2001, 393(1), 22-41.
[http://dx.doi.org/10.1006/abbi.2001.2484] [PMID: 11516158]
[38]
Xu, L.; Li, D.; Tao, L.; Yang, Y.; Li, Y.; Hou, T. Binding mechanisms of 1,4-dihydropyridine derivatives to L-type calcium channel Cav1.2: a molecular modeling study. Mol. Biosyst., 2016, 12(2), 379-390.
[http://dx.doi.org/10.1039/C5MB00781J] [PMID: 26673131]
[39]
Tikhonov, D.B.; Zhorov, B.S. Structural model for dihydropyridine binding to L-type calcium channels. J. Biol. Chem., 2009, 284(28), 19006-19017.
[http://dx.doi.org/10.1074/jbc.M109.011296] [PMID: 19416978]
[40]
Monteleone, S.; Lieb, A.; Pinggera, A.; Negro, G.; Fuchs, J.E.; Hofer, F.; Striessnig, J.; Tuluc, P.; Liedl, K.R. Mechanisms responsible for ω-pore currents in Cav calcium channel voltage-sensing domains. Biophys. J., 2017, 113(7), 1485-1495.
[http://dx.doi.org/10.1016/j.bpj.2017.08.010] [PMID: 28978442]
[41]
Feng, T.; Kalyaanamoorthy, S.; Ganesan, A.; Barakat, K. Atomistic modeling and molecular dynamics analysis of human CaV1.2 channel using external electric field and ion pulling simulations. Biochim. Biophys. Acta, Gen. Subj., 2019, 1863(6), 1116-1126.
[http://dx.doi.org/10.1016/j.bbagen.2019.04.006] [PMID: 30978379]
[42]
Carosati, E.; Cruciani, G.; Chiarini, A.; Budriesi, R.; Ioan, P.; Spisani, R.; Spinelli, D.; Cosimelli, B.; Fusi, F.; Frosini, M.; Matucci, R.; Gasparrini, F.; Ciogli, A.; Stephens, P.J.; Devlin, F.J. Calcium channel antagonists discovered by a multidisciplinary approach. J. Med. Chem., 2006, 49(17), 5206-5216.
[http://dx.doi.org/10.1021/jm0604373] [PMID: 16913709]
[43]
Baroni, M.; Cruciani, G.; Sciabola, S.; Perruccio, F.; Mason, J.S. A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for ligands and proteins (FLAP): theory and application. J. Chem. Inf. Model., 2007, 47(2), 279-294.
[http://dx.doi.org/10.1021/ci600253e] [PMID: 17381166]
[44]
Carosati, E.; Budriesi, R.; Ioan, P.; Ugenti, M.P.; Frosini, M.; Fusi, F.; Corda, G.; Cosimelli, B.; Spinelli, D.; Chiarini, A.; Cruciani, G. Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening. J. Med. Chem., 2008, 51(18), 5552-5565.
[http://dx.doi.org/10.1021/jm800151n] [PMID: 18754582]
[45]
Bergmann, R.; Linusson, A.; Zamora, I. SHOP: scaffold hopping by GRID-based similarity searches. J. Med. Chem., 2007, 50(11), 2708-2717.
[http://dx.doi.org/10.1021/jm061259g] [PMID: 17489578]
[46]
Irwin, J.J.; Shoichet, B.K. ZINC-a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID: 15667143]

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