DOI QR코드

DOI QR Code

Peptides derived from high voltage-gated calcium channel β subunit reduce blood pressure in rats

  • Hyung Kyu Kim (Department of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Jiyeon Jun (Department of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Tae Wan Kim (Department of Physiology, College of Veterinary Medicine, Kyungpook National University) ;
  • Dong-ho Youn (Department of Oral Physiology, School of Dentistry, Kyungpook National University)
  • 투고 : 2023.05.24
  • 심사 : 2023.07.03
  • 발행 : 2023.09.01

초록

The β subunits of high voltage-gated calcium channels (HGCCs) are essential for optimal channel functions such as channel gating, activation-inactivation kinetics, and trafficking to the membrane. In this study, we report for the first time the potent blood pressure-reducing effects of peptide fragments derived from the β subunits in anesthetized and non-anesthetized rats. Intravenous administration of 16-mer peptide fragments derived from the interacting regions of the β1 [cacb1(344-359)], β2 [cacb2(392-407)], β3 [cacb3(292-307)], and β4 [cacb4(333-348)] subunits with the main α-subunit of HGCC decreased arterial blood pressure in a dose-dependent manner for 5-8 min in anesthetized rats. In contrast, the peptides had no effect on the peak amplitudes of voltage-activated Ca2+ current upon their intracellular application into the acutely isolated trigeminal ganglion neurons. Further, a single mutated peptide of cacb1(344-359)-cacb1(344-359)K357R-showed consistent and potent effects and was crippled by a two-amino acid-truncation at the N-terminal or C-terminal end. By conjugating palmitic acid with the second amino acid (lysine) of cacb1(344-359)K357R (named K2-palm), we extended the blood pressure reduction to several hours without losing potency. This prolonged effect on the arterial blood pressure was also observed in non-anesthetized rats. On the other hand, the intrathecal administration of acetylated and amidated cacb1(344-359)K357R peptide did not change acute nociceptive responses induced by the intradermal formalin injection in the plantar surface of rat hindpaw. Overall, these findings will be useful for developing antihypertensives.

키워드

과제정보

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2018R1D1A1B07047469).

참고문헌

  1. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000;16:521-555.  https://doi.org/10.1146/annurev.cellbio.16.1.521
  2. Buraei Z, Yang J. The β subunit of voltage-gated Ca2+ channels. Physiol Rev. 2010;90:1461-1506.  https://doi.org/10.1152/physrev.00057.2009
  3. Altier C, Garcia-Caballero A, Simms B, You H, Chen L, Walcher J, Tedford HW, Hermosilla T, Zamponi GW. The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat Neurosci. 2011;14:173-180.  https://doi.org/10.1038/nn.2712
  4. Yang L, Katchman A, Kushner J, Kushnir A, Zakharov SI, Chen BX, Shuja Z, Subramanyam P, Liu G, Papa A, Roybal D, Pitt GS, Colecraft HM, Marx SO. Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking. J Clin Invest. 2019;129:647-658.  https://doi.org/10.1172/JCI123878
  5. Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, Yang J. Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature. 2004;429:675-680.  https://doi.org/10.1038/nature02641
  6. Opatowsky Y, Chen CC, Campbell KP, Hirsch JA. Structural analysis of the voltage-dependent calcium channel beta subunit functional core and its complex with the alpha 1 interaction domain. Neuron. 2004;42:387-399.  https://doi.org/10.1016/S0896-6273(04)00250-8
  7. Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr. Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature. 2004;429:671-675.  https://doi.org/10.1038/nature02588
  8. Hohaus A, Poteser M, Romanin C, Klugbauer N, Hofmann F, Morano I, Haase H, Groschner K. Modulation of the smooth-muscle L-type Ca2+ channel alpha1 subunit (alpha1C-b) by the beta2a subunit: a peptide which inhibits binding of beta to the I-II linker of alpha1 induces functional uncoupling. Biochem J. 2000;348 Pt 3:657-665.  https://doi.org/10.1042/bj3480657
  9. Findeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL Jr. Stapled voltage-gated calcium channel (CaV) α-interaction domain (AID) peptides act as selective protein-protein interaction inhibitors of CaV function. ACS Chem Neurosci. 2017;8:1313-1326.  https://doi.org/10.1021/acschemneuro.6b00454
  10. Viola HM, Jordan MC, Roos KP, Hool LC. Decreased myocardial injury and improved contractility after administration of a peptide derived against the alpha-interacting domain of the L-type calcium channel. J Am Heart Assoc. 2014;3:e000961. 
  11. Hardy N, Viola HM, Johnstone VP, Clemons TD, Cserne Szappanos H, Singh R, Smith NM, Iyer KS, Hool LC. Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury. ACS Nano. 2015;9:279-289.  https://doi.org/10.1021/nn5061404
  12. Clemons TD, Viola HM, House MJ, Iyer KS, Hool LC. Examining efficacy of "TAT-less" delivery of a peptide against the L-type calcium channel in cardiac ischemia-reperfusion injury. ACS Nano. 2013;7:2212-2220.  https://doi.org/10.1021/nn305211f
  13. Weon H, Jun J, Kim TW, Park K, Kim HK, Youn DH. Voltage-dependent calcium channel β subunit-derived peptides reduce excitatory neurotransmission and arterial blood pressure. Life Sci. 2021;264:118690. 
  14. Penchala SC, Miller MR, Pal A, Dong J, Madadi NR, Xie J, Joo H, Tsai J, Batoon P, Samoshin V, Franz A, Cox T, Miles J, Chan WK, Park MS, Alhamadsheh MM. A biomimetic approach for enhancing the in vivo half-life of peptides. Nat Chem Biol. 2015;11:793-798.  https://doi.org/10.1038/nchembio.1907
  15. Knudsen LB, Nielsen PF, Huusfeldt PO, Johansen NL, Madsen K, Pedersen FZ, Thogersen H, Wilken M, Agerso H. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43:1664-1669.  https://doi.org/10.1021/jm9909645
  16. Larsen MT, Kuhlmann M, Hvam ML, Howard KA. Albumin-based drug delivery: harnessing nature to cure disease. Mol Cell Ther. 2016;4:3. 
  17. Zorzi A, Middendorp SJ, Wilbs J, Deyle K, Heinis C. Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides. Nat Commun. 2017;8:16092. 
  18. Majumder K, Wu J. Molecular targets of antihypertensive peptides: understanding the mechanisms of action based on the pathophysiology of hypertension. Int J Mol Sci. 2014;16:256-283.  https://doi.org/10.3390/ijms16010256
  19. Yamada A, Sakurai T, Ochi D, Mitsuyama E, Yamauchi K, Abe F. Antihypertensive effect of the bovine casein-derived peptide MetLys-Pro. Food Chem. 2015;172:441-446.  https://doi.org/10.1016/j.foodchem.2014.09.098
  20. Tu M, Wang C, Chen C, Zhang R, Liu H, Lu W, Jiang L, Du M. Identification of a novel ACE-inhibitory peptide from casein and evaluation of the inhibitory mechanisms. Food Chem. 2018;256:98-104.  https://doi.org/10.1016/j.foodchem.2018.02.107
  21. Bhat ZF, Kumar S, Bhat HF. Antihypertensive peptides of animal origin: a review. Crit Rev Food Sci Nutr. 2017;57:566-578.  https://doi.org/10.1080/10408398.2014.898241
  22. Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20:309-325.  https://doi.org/10.1038/s41573-020-00135-8
  23. Ali MA, Rizvi S, Syed BA. Trends in the market for antihypertensive drugs. Nat Rev Drug Discov. 2017;16:309-310.  https://doi.org/10.1038/nrd.2016.262
  24. Merrifield RB. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J Am Chem Soc. 1963;85:2149-2154. https://doi.org/10.1021/ja00897a025