The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Ca2+/calmodulin-dependent regulation of polycystic kidney disease 2-like-1 by binding at C-terminal domain

  • Baik, Julia Young (Department of Physiology, Seoul National University College of Medicine) ;
  • Park, Eunice Yon June (Department of Physiology, Seoul National University College of Medicine) ;
  • So, Insuk (Department of Physiology, Seoul National University College of Medicine)
  • Received : 2020.01.07
  • Accepted : 2020.02.26
  • Published : 2020.05.01
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Abstract

Polycystic kidney disease 2-like-1 (PKD2L1), also known as polycystin-L or TRPP3, is a non-selective cation channel that regulates intracellular calcium concentration. Calmodulin (CaM) is a calcium binding protein, consisting of N-lobe and C-lobe with two calcium binding EF-hands in each lobe. In previous study, we confirmed that CaM is associated with desensitization of PKD2L1 and that CaM N-lobe and PKD2L1 EF-hand specifically are involved. However, the CaM-binding domain (CaMBD) and its inhibitory mechanism of PKD2L1 have not been identified. In order to identify CaM-binding anchor residue of PKD2L1, single mutants of putative CaMBD and EF-hand deletion mutants were generated. The current changes of the mutants were recorded with whole-cell patch clamp. The calmidazolium (CMZ), a calmodulin inhibitor, was used under different concentrations of intracellular. Among the mutants that showed similar or higher basal currents with that of the PKD2L1 wild type, L593A showed little change in current induced by CMZ. Co-expression of L593A with CaM attenuated the inhibitory effect of PKD2L1 by CaM. In the previous study it was inferred that CaM C-lobe inhibits channels by binding to PKD2L1 at 16 nM calcium concentration and CaM N-lobe at 100 nM. Based on the results at 16 nM calcium concentration condition, this study suggests that CaM C-lobe binds to Leu-593, which can be a CaM C-lobe anchor residue, to regulate channel activity. Taken together, our results provide a model for the regulation of PKD2L1 channel activity by CaM.

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References

  1. Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE. Primary cilia are specialized calcium signalling organelles. Nature. 2013;504:311-314. https://doi.org/10.1038/nature12833
  2. Sternberg JR, Prendergast AE, Brosse L, Cantaut-Belarif Y, Thouvenin O, Orts-Del'Immagine A, Castillo L, Djenoune L, Kurisu S, McDearmid JR, Bardet PL, Boccara C, Okamoto H, Delmas P, Wyart C. Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature. Nat Commun. 2018;9:3804. https://doi.org/10.1038/s41467-018-06225-x
  3. DeCaen PG, Delling M, Vien TN, Clapham DE. Direct recording and molecular identification of the calcium channel of primary cilia. Nature. 2013;504:315-318. https://doi.org/10.1038/nature12832
  4. Ishimaru Y, Inada H, Kubota M, Zhuang H, Tominaga M, Matsunami H. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci U S A. 2006;103:12569-12574. https://doi.org/10.1073/pnas.0602702103
  5. Zheng W, Hussein S, Yang J, Huang J, Zhang F, Hernandez-Anzaldo S, Fernandez-Patron C, Cao Y, Zeng H, Tang J, Chen XZ. A novel PKD2L1 C-terminal domain critical for trimerization and channel function. Sci Rep. 2015;5:9460. https://doi.org/10.1038/srep09460
  6. DeCaen PG, Liu X, Abiria S, Clapham DE. Atypical calcium regulation of the PKD2-L1 polycystin ion channel. Elife. 2016;5:e13413. https://doi.org/10.7554/elife.13413
  7. Park EYJ, Kwak M, Ha K, So I. Identification of clustered phosphorylation sites in PKD2L1: how PKD2L1 channel activation is regulated by cyclic adenosine monophosphate signaling pathway. Pflugers Arch. 2018;470:505-516. https://doi.org/10.1007/s00424-017-2095-7
  8. Su Q, Hu F, Liu Y, Ge X, Mei C, Yu S, Shen A, Zhou Q, Yan C, Lei J, Zhang Y, Liu X, Wang T. Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1. Nat Commun. 2018;9:1192. https://doi.org/10.1038/s41467-018-03606-0
  9. Hulse RE, Li Z, Huang RK, Zhang J, Clapham DE. Cryo-EM structure of the polycystin 2-l1 ion channel. Elife. 2018;7:e36931. https://doi.org/10.7554/elife.36931
  10. Chattopadhyaya R, Meador WE, Means AR, Quiocho FA. Calmodulin structure refined at 1.7 A resolution. J Mol Biol. 1992;228:1177-1192. https://doi.org/10.1016/0022-2836(92)90324-D
  11. Urrutia J, Aguado A, Muguruza-Montero A, Nunez E, Malo C, Casis O, Villarroel A. The crossroad of ion channels and calmodulin in disease. Int J Mol Sci. 2019;20:E400.
  12. Martin SR, Andersson Teleman A, Bayley PM, Drakenberg T, Forsen S. Kinetics of calcium dissociation from calmodulin and its tryptic fragments. A stopped-flow fluorescence study using Quin 2 reveals a two-domain structure. Eur J Biochem. 1985;151:543-550. https://doi.org/10.1111/j.1432-1033.1985.tb09137.x
  13. Liu XR, Zhang MM, Rempel DL, Gross ML. A single approach reveals the composite conformational changes, order of binding, and affinities for calcium binding to calmodulin. Anal Chem. 2019;91:5508-5512. https://doi.org/10.1021/acs.analchem.9b01062
  14. Kawasaki H, Soma N, Kretsinger RH. Molecular dynamics study of the changes in conformation of calmodulin with calcium binding and/or target recognition. Sci Rep. 2019;9:10688. https://doi.org/10.1038/s41598-019-47063-1
  15. Saimi Y, Kung C. Calmodulin as an ion channel subunit. Annu Rev Physiol. 2002;64:289-311. https://doi.org/10.1146/annurev.physiol.64.100301.111649
  16. Kovalevskaya NV, van de Waterbeemd M, Bokhovchuk FM, Bate N, Bindels RJ, Hoenderop JG, Vuister GW. Structural analysis of calmodulin binding to ion channels demonstrates the role of its plasticity in regulation. Pflugers Arch. 2013;465:1507-1519. https://doi.org/10.1007/s00424-013-1278-0
  17. Shah VN, Chagot B, Chazin WJ. Calcium-dependent regulation of ion channels. Calcium Bind Proteins. 2006;1:203-212.
  18. Budde T, Meuth S, Pape HC. Calcium-dependent inactivation of neuronal calcium channels. Nat Rev Neurosci. 2002;3:873-883. https://doi.org/10.1038/nrn959
  19. Lee CH, MacKinnon R. Activation mechanism of a human SKcalmodulin channel complex elucidated by cryo-EM structures. Science. 2018;360:508-513. https://doi.org/10.1126/science.aas9466
  20. Wang C, Chung BC, Yan H, Wang HG, Lee SY, Pitt GS. Structural analyses of $Ca^{2+}$/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation. Nat Commun. 2014;5:4896. https://doi.org/10.1038/ncomms5896
  21. Shah VN, Wingo TL, Weiss KL, Williams CK, Balser JR, Chazin WJ. Calcium-dependent regulation of the voltage-gated sodium channel hH1: intrinsic and extrinsic sensors use a common molecular switch. Proc Natl Acad Sci U S A. 2006;103:3592-3597. https://doi.org/10.1073/pnas.0507397103
  22. Ben Johny M, Yang PS, Bazzazi H, Yue DT. Dynamic switching of calmodulin interactions underlies $Ca^{2+}$ regulation of CaV1.3 channels. Nat Commun. 2013;4:1717. https://doi.org/10.1038/ncomms2727
  23. Gordon-Shaag A, Zagotta WN, Gordon SE. Mechanism of $Ca^{2+}$-dependent desensitization in TRP channels. Channels (Austin). 2008;2:125-129. https://doi.org/10.4161/chan.2.2.6026
  24. Hasan R, Leeson-Payne AT, Jaggar JH, Zhang X. Calmodulin is responsible for $Ca^{2+}$-dependent regulation of TRPA1 channels. Sci Rep. 2017;7:45098. https://doi.org/10.1038/srep45098
  25. Zhu MX. Multiple roles of calmodulin and other $Ca^{2+}$-binding proteins in the functional regulation of TRP channels. Pflugers Arch. 2005;451:105-115. https://doi.org/10.1007/s00424-005-1427-1
  26. Polat OK, Uno M, Maruyama T, Tran HN, Imamura K, Wong CF, Sakaguchi R, Ariyoshi M, Itsuki K, Ichikawa J, Morii T, Shirakawa M, Inoue R, Asanuma K, Reiser J, Tochio H, Mori Y, Mori MX. Contribution of coiled-coil assembly to $Ca^{2+}$/calmodulin-dependent inactivation of TRPC6 channel and its impacts on FSGS-associated phenotypes. J Am Soc Nephrol. 2019;30:1587-1603. https://doi.org/10.1681/ASN.2018070756
  27. Dang S, van Goor MK, Asarnow D, Wang Y, Julius D, Cheng Y, van der Wijst J. Structural insight into TRPV5 channel function and modulation. Proc Natl Acad Sci U S A. 2019;116:8869-8878. https://doi.org/10.1073/pnas.1820323116
  28. Singh AK, McGoldrick LL, Twomey EC, Sobolevsky AI. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Sci Adv. 2018;4:eaau6088. https://doi.org/10.1126/sciadv.aau6088
  29. Park EYJ, Baik JY, Kwak M, So I. The role of calmodulin in regulating calcium-permeable PKD2L1 channel activity. Korean J Physiol Pharmacol. 2019;23:219-227. https://doi.org/10.4196/kjpp.2019.23.3.219
  30. Hoeflich KP, Ikura M. Calmodulin in action: diversity in target recognition and activation mechanisms. Cell. 2002;108:739-742. https://doi.org/10.1016/S0092-8674(02)00682-7
  31. Tidow H, Nissen P. Structural diversity of calmodulin binding to its target sites. FEBS J. 2013;280:5551-5565. https://doi.org/10.1111/febs.12296
  32. Mruk K, Farley BM, Ritacco AW, Kobertz WR. Calmodulation meta-analysis: predicting calmodulin binding via canonical motif clustering. J Gen Physiol. 2014;144:105-114. https://doi.org/10.1085/jgp.201311140
  33. Sunagawa M, Kosugi T, Nakamura M, Sperelakis N. Pharmacological actions of calmidazolium, a calmodulin antagonist, in cardiovascular system. Cardiovasc Drug Rev. 2000;18:211-221. https://doi.org/10.1111/j.1527-3466.2000.tb00044.x
  34. Kumar S, Kain V, Sitasawad SL. Cardiotoxicity of calmidazolium chloride is attributed to calcium aggravation, oxidative and nitrosative stress, and apoptosis. Free Radic Biol Med. 2009;47:699-709. https://doi.org/10.1016/j.freeradbiomed.2009.05.028
  35. Lau SY, Procko E, Gaudet R. Distinct properties of $Ca^{2+}$-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J Gen Physiol. 2012;140:541-555. https://doi.org/10.1085/jgp.201210810