Institute of Biochemistry and Molecular Medicine

Group Peinelt

Peinelt Group — Peinelt group from the left to the right: Anna Borgström, Irida Papapostolou, Korollus Melek, Sven Kappel, María Constanza Maldifassi, Dani Ross-Kaschitza, Paulina Stokłosa, Christine Peinelt, Barbara Hauert, Florian Bochen

Research Focus:

Changes in the intracellular calcium concentration play a critical role in cellular responses to cues from the extracellular environment. One influx route for slower and long lasting changes in [Ca2+] involve the release of Ca2+ from intracellular stores and entry of extracellular Ca2+. Depletion of distinct Ca2+ stores results in store-operated Ca2+ entry (SOCE). The best studied SOC current is the Calcium Release Activated Calcium current (ICRAC). ICRAC plays an important role in many cellular processes e.g. gene expression and cell proliferation.

Our group works on the molecular components of ICRAC (CRACM = Orai1, 2 und 3 Ca2+ channels, sensor proteins (stromal interaction molecule) STIM1 und STIM2). We are interested in structure/function relationship and dysregulation of SOCE signals in the pathophysiology of cancer and immune disease.

The main focus of our group is the transient receptor potential melastatin-4 channel (TRPM4). We and others demonstrated that TRPM4 expression levels are elevated in human prostate cancer tissue. In prostate cancer cells, TRPM4-mediated Na+ influx can depolarize the membrane potential, decreasing the driving force for Ca2+ and reducing SOCE signals as a feedback mechanism. In addition, TRPM4 contributes to migration of prostate cancer cells, which is one of the initial steps to metastasis. Our group aims to investigate the physiological and pathophysiological consequences of TRPM4 impairments in prostate cancer cells.

Highlights:

Physiology/Pathophysiology of ion channels
Pharmacology of Ca2+ signals, STIM/Orai, TRPM4
Ion channels as future therapeutic targets
Electrophysiology, BioImaging, Ca2+ Imaging, cell assays
Human primary prostate epithelial cells/tissues
Immune system
Prostate cancer

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Publications

1: Schild A, Bhardwaj R, Wenger N, Tscherrig D, Kandasamy P, Dernič J, Baur R, Peinelt C, Hediger MA, Lochner M.
Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store- Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. Int J Mol Sci. 2020 Aug 5;21(16):E5604. doi: 10.3390/ijms21165604. PMID: 32764353.

2: Stokłosa P, Probst D, Reymond JL, Peinelt C.
The name tells the story: Two- pore channels. Cell Calcium. 2020 Jul;89:102215. doi: 10.1016/j.ceca.2020.102215. Epub 2020 May 11. PMID: 32442744.

3: Kappel S, Kilch T, Baur R, Lochner M, Peinelt C.
The Number and Position of Orai3 Units within Heteromeric Store-Operated Ca²⁺ Channels Alter the Pharmacology of I_CRAC. Int J Mol Sci. 2020 Apr 2;21(7):2458. doi: 10.3390/ijms21072458. PMID: 32252254; PMCID: PMC7178029.

4: Stokłosa P, Borgström A, Kappel S, Peinelt C.
TRP Channels in Digestive Tract Cancers. Int J Mol Sci. 2020 Mar 9;21(5):1877. doi: 10.3390/ijms21051877. PMID: 32182937; PMCID: PMC7084354.

5: Bhardwaj R, Augustynek BS, Ercan-Herbst E, Kandasamy P, Seedorf M, Peinelt C , Hediger MA.
Ca²⁺/Calmodulin Binding to STIM1 Hydrophobic Residues Facilitates Slow Ca²⁺-Dependent Inactivation of the Orai1 Channel. Cell Physiol Biochem. 2020 Mar 17;54(2):252-270. doi: 10.33594/000000218. PMID: 32176842.

6: Kappel S, Stokłosa P, Hauert B, Ross-Kaschitza D, Borgström A, Baur R, Galván JA, Zlobec I, Peinelt C.
TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells. Mol Oncol. 2019 Nov;13(11):2393-2405. doi: 10.1002/1878-0261.12566. Epub 2019 Sep 12. PMID: 31441200; PMCID: PMC6822246.

7: Kappel S, Borgström A, Stokłosa P, Dörr K, Peinelt C.
Store-operated calcium entry in disease: Beyond STIM/Orai expression levels. Semin Cell Dev Biol. 2019 Oct;94:66-73. doi: 10.1016/j.semcdb.2019.01.003. Epub 2019 Jan 12. PMID: 30630032.

8: Ozhathil LC, Delalande C, Bianchi B, Nemeth G, Kappel S, Thomet U, Ross- Kaschitza D, Simonin C, Rubin M, Gertsch J, Lochner M, Peinelt C, Reymond JL, Abriel H.
Identification of potent and selective small molecule inhibitors of the cation channel TRPM4. Br J Pharmacol. 2018 Jun;175(12):2504-2519. doi: 10.1111/bph.14220. Epub 2018 Apr 29. PMID: 29579323; PMCID: PMC6002741.

9: Kappel S, Marques IJ, Zoni E, Stokłosa P,Peinelt C, Mercader N, Kruithof-de Julio M, Borgström A.
Correction to: Store-Operated Ca²⁺ Entry as a Prostate Cancer Biomarker - a Riddle with Perspectives. Curr Mol Biol Rep. 2018;4(3):142. doi: 10.1007/s40610-018-0097-7. Epub 2018 Jun 20. Erratum for: Curr Mol Biol Rep. 2017;3(4):208-217. PMID: 31187023; PMCID: PMC6096868.

10: Kappel S, Marques IJ, Zoni E, Stokłosa P, Peinelt C, Mercader N, Kruithof-de Julio M, Borgström A.
Store-Operated Ca²⁺ Entry as a Prostate Cancer Biomarker - a Riddle with Perspectives. Curr Mol Biol Rep. 2017;3(4):208-217. doi: 10.1007/s40610-017-0072-8. Epub 2017 Oct 28. Erratum in: Curr Mol Biol Rep. 2018;4(3):142. PMID: 29951353; PMCID: PMC6010502.

11: Dörr K, Kilch T, Kappel S, Alansary D, Schwär G, Niemeyer BA, Peinelt C.
Cell type-specific glycosylation of Orai1 modulates store-operated Ca2+ entry. Sci Signal. 2016 Mar 8;9(418):ra25. doi: 10.1126/scisignal.aaa9913. PMID: 26956484.

12: Kilch T, Kappel S, Peinelt C.
Regulation of Ca(2+) signaling in prostate cancer cells. Channels (Austin). 2016;10(3):170-1. doi: 10.1080/19336950.2015.1137176. Epub 2016 Jan 8. PMID: 26745455; PMCID: PMC4954580.

13: Holzmann C, Kappel S, Kilch T, Jochum MM, Urban SK, Jung V, Stöckle M, Rother K, Greiner M, Peinelt C.
Transient receptor potential melastatin 4 channel contributes to migration of androgen-insensitive prostate cancer cells. Oncotarget. 2015 Dec 8;6(39):41783-93. doi: 10.18632/oncotarget.6157. PMID: 26496025; PMCID: PMC4747188.

14: Holzmann C, Kilch T, Kappel S, Dörr K, Jung V, Stöckle M, Bogeski I,Peinelt C.
Differential Redox Regulation of Ca²⁺ Signaling and Viability in Normal and Malignant Prostate Cells. Biophys J. 2015 Oct 6;109(7):1410-9. doi: 10.1016/j.bpj.2015.08.006. PMID: 26445441; PMCID: PMC4601090.

15: Beck A, Fleig A, Penner R,Peinelt C.
Regulation of endogenous and heterologous Ca²⁺ release-activated Ca²⁺ currents by pH. Cell Calcium. 2014 Sep;56(3):235-43. doi: 10.1016/j.ceca.2014.07.011. Epub 2014 Aug 2. PMID: 25168908; PMCID: PMC4162834.

16: Alansary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A.
Patch-clamp measurement of ICRAC and ORAI channel activity. Cold Spring Harb Protoc. 2014 Jun 2;2014(6):602-7. doi: 10.1101/pdb.top066795. PMID: 24890214.

17: Alansary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A.
The minimal requirements to use calcium imaging to analyze ICRAC. Cold Spring Harb Protoc. 2014 Jun 2;2014(6):638-42. doi: 10.1101/pdb.prot073262. PMID: 24890204.

18: Alansary D, Kilch T, Holzmann C,Peinelt C, Hoth M, Lis A.
Measuring endogenous ICRAC and ORAI currents with the patch-clamp technique. Cold Spring Harb Protoc. 2014 Jun 2;2014(6):630-7. doi: 10.1101/pdb.prot073254. PMID: 24890203.

19: Holzmann C, Kilch T, Kappel S, Armbrüster A, Jung V, Stöckle M, Bogeski I, Schwarz EC, Peinelt C.
ICRAC controls the rapid androgen response in human primary prostate epithelial cells and is altered in prostate cancer. Oncotarget. 2013 Nov;4(11):2096-107. doi: 10.18632/oncotarget.1483. PMID: 24240085; PMCID: PMC3875772.

20: Kilch T, Alansary D, Peglow M, Dörr K, Rychkov G, Rieger H,Peinelt C, Niemeyer BA.
Mutations of the Ca2+-sensing stromal interaction molecule STIM1 regulate Ca2+ influx by altered oligomerization of STIM1 and by destabilization of the Ca2+ channel Orai1. J Biol Chem. 2013 Jan 18;288(3):1653-64. doi: 10.1074/jbc.M112.417246. Epub 2012 Dec 4. PMID: 23212906; PMCID: PMC3548475.

21: Carreras-Sureda A, Cantero-Recasens G, Rubio-Moscardo F, Kiefer K, Peinelt C, Niemeyer BA, Valverde MA, Vicente R.
ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Hum Mol Genet. 2013 Feb 1;22(3):519-30. doi: 10.1093/hmg/dds450. Epub 2012 Oct 25. PMID: 23100328.

22: Stanisz H, Stark A, Kilch T, Schwarz EC, Müller CS, Peinelt C, Hoth M, Niemeyer BA, Vogt T, Bogeski I.
ORAI1 Ca(2+) channels control endothelin-1-induced mitogenesis and melanogenesis in primary human melanocytes. J Invest Dermatol. 2012 May;132(5):1443-51. doi: 10.1038/jid.2011.478. Epub 2012 Feb 9. PMID: 22318387.

23: Lis A, Zierler S, Peinelt C, Fleig A, Penner R.
A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J Gen Physiol. 2010 Dec;136(6):673-86. doi: 10.1085/jgp.201010484. PMID: 21115697; PMCID: PMC2995155.

24: Bogeski I, Al-Ansary D, Qu B, Niemeyer BA, Hoth M, Peinelt C.
Pharmacology of ORAI channels as a tool to understand their physiological functions. Expert Rev Clin Pharmacol. 2010 May;3(3):291-303. doi: 10.1586/ecp.10.23. PMID: 22111611.

25: Bogeski I, Kummerow C, Al-Ansary D, Schwarz EC, Koehler R, Kozai D, Takahashi N, Peinelt C, Griesemer D, Bozem M, Mori Y, Hoth M, Niemeyer BA.
Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling. Sci Signal. 2010 Mar 30;3(115):ra24. doi: 10.1126/scisignal.2000672. PMID: 20354224.

26: Peinelt C, Beck A, Monteilh-Zoller MK, Penner R, Fleig A.
IP(3) receptor subtype-dependent activation of store-operated calcium entry through I(CRAC). Cell Calcium. 2009 Apr;45(4):326-30. doi: 10.1016/j.ceca.2008.12.001. Epub 2009 Jan 20. PMID: 19157540; PMCID: PMC2744131.

27: Peinelt C, Lis A, Beck A, Fleig A, Penner R.
2-Aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels. J Physiol. 2008 Jul 1;586(13):3061-73. doi: 10.1113/jphysiol.2008.151365. Epub 2008 Apr 10. PMID: 18403424; PMCID: PMC2538778.

28: Parvez S, Beck A, Peinelt C, Soboloff J, Lis A, Monteilh-Zoller M, Gill DL, Fleig A, Penner R.
STIM2 protein mediates distinct store-dependent and store- independent modes of CRAC channel activation. FASEB J. 2008 Mar;22(3):752-61. doi: 10.1096/fj.07-9449com. Epub 2007 Sep 28. PMID: 17905723; PMCID: PMC3601890.

29: Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R.
CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol. 2007 May 1;17(9):794-800. doi: 10.1016/j.cub.2007.03.065. Epub 2007 Apr 19. PMID: 17442569; PMCID: PMC5663639.

30: Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R. CRACM1 multimers form the ion- selective pore of the CRAC channel. Curr Biol. 2006 Oct 24;16(20):2073-9. doi: 10.1016/j.cub.2006.08.085. Epub 2006 Sep 14. PMID: 16978865; PMCID: PMC5685803.

31: Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP.
Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol. 2006 Jul;8(7):771-3. doi: 10.1038/ncb1435. Epub 2006 May 30. PMID: 16733527; PMCID: PMC5685802.

32: Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP.
CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science. 2006 May 26;312(5777):1220-3. doi: 10.1126/science.1127883. Epub 2006 Apr 27. PMID: 16645049; PMCID: PMC5685805.

33: Peinelt C, Apell HJ.
Kinetics of Ca2+ binding to the SR Ca-ATPase in the E1 state. Biophys J. 2005 Oct;89(4):2427-33. doi: 10.1529/biophysj.105.068411. Epub 2005 Jul 22. PMID: 16040761; PMCID: PMC1366742.

34: Peinelt C, Apell HJ.
Time-resolved charge movements in the sarcoplasmatic reticulum Ca-ATPase. Biophys J. 2004 Feb;86(2):815-24. doi: 10.1016/S0006-3495(04)74157-0. PMID: 14747317; PMCID: PMC1303929.

35: Peinelt C, Apell HJ.
Time-resolved partial reactions of the SR Ca-ATPase investigated with a fluorescent styryl dye. Ann N Y Acad Sci. 2003 Apr;986:325-6. doi: 10.1111/j.1749-6632.2003.tb07203.x. PMID: 12763839.

36: Peinelt C, Apell HJ.
Kinetics of the Ca(2+), H(+), and Mg(2+) interaction with the ion-binding sites of the SR Ca-ATPase. Biophys J. 2002 Jan;82(1 Pt 1):170-81. doi: 10.1016/S0006-3495(02)75384-8. PMID: 11751306; PMCID: PMC1302459.