Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2001 Sep;81(3):1419–1429. doi: 10.1016/S0006-3495(01)75797-9

Two domains in dihydropyridine receptor activate the skeletal muscle Ca(2+) release channel.

M Stange 1, A Tripathy 1, G Meissner 1
PMCID: PMC1301621  PMID: 11509356

Abstract

The II-III cytoplasmic loop of the skeletal muscle dihydropyridine receptor (DHPR) alpha(1)-subunit is essential for skeletal-type excitation-contraction coupling. Single channel and [(3)H]ryanodine binding studies with a full-length recombinant peptide (p(666-791)) confirmed that this region specifically activates skeletal muscle Ca2+ release channels (CRCs). However, attempts to identify shorter domains of the II-III loop specific for skeletal CRC activation have yielded contradictory results. We assessed the specificity of the interaction of five truncated II-III loop peptides by comparing their effects on skeletal and cardiac CRCs in lipid bilayer experiments; p(671-680) and p(720-765) specifically activated the submaximally Ca2+-activated skeletal CRC in experiments using both mono and divalent ions as current carriers. A third peptide, p(671-690), showed a bimodal activation/inactivation behavior indicating a high-affinity activating and low-affinity inactivating binding site. Two other peptides (p(681-690) and p(681-685)) that contained an RKRRK-motif and have previously been suggested in in vitro studies to be important for skeletal-type E-C coupling, failed to specifically stimulate skeletal CRCs. Noteworthy, p(671-690), p(681-690), and p(681-685) induced similar subconductances and long-lasting channel closings in skeletal and cardiac CRCs, indicating that these peptides interact in an isoform-independent manner with the CRCs.

Full Text

The Full Text of this article is available as a PDF (188.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beurg M., Ahern C. A., Vallejo P., Conklin M. W., Powers P. A., Gregg R. G., Coronado R. Involvement of the carboxy-terminus region of the dihydropyridine receptor beta1a subunit in excitation-contraction coupling of skeletal muscle. Biophys J. 1999 Dec;77(6):2953–2967. doi: 10.1016/S0006-3495(99)77128-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Block B. A., Imagawa T., Campbell K. P., Franzini-Armstrong C. Structural evidence for direct interaction between the molecular components of the transverse tubule/sarcoplasmic reticulum junction in skeletal muscle. J Cell Biol. 1988 Dec;107(6 Pt 2):2587–2600. doi: 10.1083/jcb.107.6.2587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Casarotto M. G., Gibson F., Pace S. M., Curtis S. M., Mulcair M., Dulhunty A. F. A structural requirement for activation of skeletal ryanodine receptors by peptides of the dihydropyridine receptor II-III loop. J Biol Chem. 2000 Apr 21;275(16):11631–11637. doi: 10.1074/jbc.275.16.11631. [DOI] [PubMed] [Google Scholar]
  4. Catterall W. A. Structure and function of voltage-gated ion channels. Annu Rev Biochem. 1995;64:493–531. doi: 10.1146/annurev.bi.64.070195.002425. [DOI] [PubMed] [Google Scholar]
  5. Coronado R., Morrissette J., Sukhareva M., Vaughan D. M. Structure and function of ryanodine receptors. Am J Physiol. 1994 Jun;266(6 Pt 1):C1485–C1504. doi: 10.1152/ajpcell.1994.266.6.C1485. [DOI] [PubMed] [Google Scholar]
  6. Dulhunty A. F., Laver D. R., Gallant E. M., Casarotto M. G., Pace S. M., Curtis S. Activation and inhibition of skeletal RyR channels by a part of the skeletal DHPR II-III loop: effects of DHPR Ser687 and FKBP12. Biophys J. 1999 Jul;77(1):189–203. doi: 10.1016/S0006-3495(99)76881-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. El-Hayek R., Ikemoto N. Identification of the minimum essential region in the II-III loop of the dihydropyridine receptor alpha 1 subunit required for activation of skeletal muscle-type excitation-contraction coupling. Biochemistry. 1998 May 12;37(19):7015–7020. doi: 10.1021/bi972907o. [DOI] [PubMed] [Google Scholar]
  8. Franzini-Armstrong C., Protasi F. Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. Physiol Rev. 1997 Jul;77(3):699–729. doi: 10.1152/physrev.1997.77.3.699. [DOI] [PubMed] [Google Scholar]
  9. Gurrola G. B., Arévalo C., Sreekumar R., Lokuta A. J., Walker J. W., Valdivia H. H. Activation of ryanodine receptors by imperatoxin A and a peptide segment of the II-III loop of the dihydropyridine receptor. J Biol Chem. 1999 Mar 19;274(12):7879–7886. doi: 10.1074/jbc.274.12.7879. [DOI] [PubMed] [Google Scholar]
  10. Lee H. B., Xu L., Meissner G. Reconstitution of the skeletal muscle ryanodine receptor-Ca2+ release channel protein complex into proteoliposomes. J Biol Chem. 1994 May 6;269(18):13305–13312. [PubMed] [Google Scholar]
  11. Leong P., MacLennan D. H. The cytoplasmic loops between domains II and III and domains III and IV in the skeletal muscle dihydropyridine receptor bind to a contiguous site in the skeletal muscle ryanodine receptor. J Biol Chem. 1998 Nov 6;273(45):29958–29964. doi: 10.1074/jbc.273.45.29958. [DOI] [PubMed] [Google Scholar]
  12. Lu X., Xu L., Meissner G. Activation of the skeletal muscle calcium release channel by a cytoplasmic loop of the dihydropyridine receptor. J Biol Chem. 1994 Mar 4;269(9):6511–6516. [PubMed] [Google Scholar]
  13. Marty I., Robert M., Villaz M., De Jongh K., Lai Y., Catterall W. A., Ronjat M. Biochemical evidence for a complex involving dihydropyridine receptor and ryanodine receptor in triad junctions of skeletal muscle. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2270–2274. doi: 10.1073/pnas.91.6.2270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mead F. C., Sullivan D., Williams A. J. Evidence for negative charge in the conduction pathway of the cardiac ryanodine receptor channel provided by the interaction of K+ channel N-type inactivation peptides. J Membr Biol. 1998 Jun 1;163(3):225–234. doi: 10.1007/s002329900386. [DOI] [PubMed] [Google Scholar]
  15. Meissner G. Adenine nucleotide stimulation of Ca2+-induced Ca2+ release in sarcoplasmic reticulum. J Biol Chem. 1984 Feb 25;259(4):2365–2374. [PubMed] [Google Scholar]
  16. Meissner G., Henderson J. S. Rapid calcium release from cardiac sarcoplasmic reticulum vesicles is dependent on Ca2+ and is modulated by Mg2+, adenine nucleotide, and calmodulin. J Biol Chem. 1987 Mar 5;262(7):3065–3073. [PubMed] [Google Scholar]
  17. Meissner G. Ryanodine receptor/Ca2+ release channels and their regulation by endogenous effectors. Annu Rev Physiol. 1994;56:485–508. doi: 10.1146/annurev.ph.56.030194.002413. [DOI] [PubMed] [Google Scholar]
  18. Murray B. E., Ohlendieck K. Cross-linking analysis of the ryanodine receptor and alpha1-dihydropyridine receptor in rabbit skeletal muscle triads. Biochem J. 1997 Jun 1;324(Pt 2):689–696. doi: 10.1042/bj3240689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nakai J., Tanabe T., Konno T., Adams B., Beam K. G. Localization in the II-III loop of the dihydropyridine receptor of a sequence critical for excitation-contraction coupling. J Biol Chem. 1998 Sep 25;273(39):24983–24986. doi: 10.1074/jbc.273.39.24983. [DOI] [PubMed] [Google Scholar]
  20. Ondrias K., Marx S. O., Gaburjakova M., Marks A. R. FKBP12 modulates gating of the ryanodine receptor/calcium release channel. Ann N Y Acad Sci. 1998 Sep 16;853:149–156. doi: 10.1111/j.1749-6632.1998.tb08263.x. [DOI] [PubMed] [Google Scholar]
  21. Proenza C., Wilkens C. M., Beam K. G. Excitation-contraction coupling is not affected by scrambled sequence in residues 681-690 of the dihydropyridine receptor II-III loop. J Biol Chem. 2000 Sep 29;275(39):29935–29937. doi: 10.1074/jbc.C000464200. [DOI] [PubMed] [Google Scholar]
  22. Protasi F., Franzini-Armstrong C., Allen P. D. Role of ryanodine receptors in the assembly of calcium release units in skeletal muscle. J Cell Biol. 1998 Feb 23;140(4):831–842. doi: 10.1083/jcb.140.4.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Radermacher M., Rao V., Grassucci R., Frank J., Timerman A. P., Fleischer S., Wagenknecht T. Cryo-electron microscopy and three-dimensional reconstruction of the calcium release channel/ryanodine receptor from skeletal muscle. J Cell Biol. 1994 Oct;127(2):411–423. doi: 10.1083/jcb.127.2.411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ríos E., Pizarro G. Voltage sensor of excitation-contraction coupling in skeletal muscle. Physiol Rev. 1991 Jul;71(3):849–908. doi: 10.1152/physrev.1991.71.3.849. [DOI] [PubMed] [Google Scholar]
  25. Saiki Y., El-Hayek R., Ikemoto N. Involvement of the Glu724-Pro760 region of the dihydropyridine receptor II-III loop in skeletal muscle-type excitation-contraction coupling. J Biol Chem. 1999 Mar 19;274(12):7825–7832. doi: 10.1074/jbc.274.12.7825. [DOI] [PubMed] [Google Scholar]
  26. Samsó M., Trujillo R., Gurrola G. B., Valdivia H. H., Wagenknecht T. Three-dimensional location of the imperatoxin A binding site on the ryanodine receptor. J Cell Biol. 1999 Jul 26;146(2):493–499. doi: 10.1083/jcb.146.2.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schoenmakers T. J., Visser G. J., Flik G., Theuvenet A. P. CHELATOR: an improved method for computing metal ion concentrations in physiological solutions. Biotechniques. 1992 Jun;12(6):870-4, 876-9. [PubMed] [Google Scholar]
  28. Serysheva I. I., Orlova E. V., Chiu W., Sherman M. B., Hamilton S. L., van Heel M. Electron cryomicroscopy and angular reconstitution used to visualize the skeletal muscle calcium release channel. Nat Struct Biol. 1995 Jan;2(1):18–24. doi: 10.1038/nsb0195-18. [DOI] [PubMed] [Google Scholar]
  29. Slavik K. J., Wang J. P., Aghdasi B., Zhang J. Z., Mandel F., Malouf N., Hamilton S. L. A carboxy-terminal peptide of the alpha 1-subunit of the dihydropyridine receptor inhibits Ca(2+)-release channels. Am J Physiol. 1997 May;272(5 Pt 1):C1475–C1481. doi: 10.1152/ajpcell.1997.272.5.C1475. [DOI] [PubMed] [Google Scholar]
  30. Takekura H., Franzini-Armstrong C. Correct targeting of dihydropyridine receptors and triadin in dyspedic mouse skeletal muscle in vivo. Dev Dyn. 1999 Apr;214(4):372–380. doi: 10.1002/(SICI)1097-0177(199904)214:4<372::AID-AJA9>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  31. Tanabe T., Beam K. G., Adams B. A., Niidome T., Numa S. Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature. 1990 Aug 9;346(6284):567–569. doi: 10.1038/346567a0. [DOI] [PubMed] [Google Scholar]
  32. Tinker A., Lindsay A. R., Williams A. J. Large tetraalkyl ammonium cations produce a reduced conductance state in the sheep cardiac sarcoplasmic reticulum Ca(2+)-release channel. Biophys J. 1992 May;61(5):1122–1132. doi: 10.1016/S0006-3495(92)81922-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tinker A., Williams A. J. Charged local anesthetics block ionic conduction in the sheep cardiac sarcoplasmic reticulum calcium release channel. Biophys J. 1993 Aug;65(2):852–864. doi: 10.1016/S0006-3495(93)81104-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tripathy A., Meissner G. Sarcoplasmic reticulum lumenal Ca2+ has access to cytosolic activation and inactivation sites of skeletal muscle Ca2+ release channel. Biophys J. 1996 Jun;70(6):2600–2615. doi: 10.1016/S0006-3495(96)79831-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tripathy A., Resch W., Xu L., Valdivia H. H., Meissner G. Imperatoxin A induces subconductance states in Ca2+ release channels (ryanodine receptors) of cardiac and skeletal muscle. J Gen Physiol. 1998 May;111(5):679–690. doi: 10.1085/jgp.111.5.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Xiong H., Feng X., Gao L., Xu L., Pasek D. A., Seok J. H., Meissner G. Identification of a two EF-hand Ca2+ binding domain in lobster skeletal muscle ryanodine receptor/Ca2+ release channel. Biochemistry. 1998 Apr 7;37(14):4804–4814. doi: 10.1021/bi971198b. [DOI] [PubMed] [Google Scholar]
  37. Xu L., Jones R., Meissner G. Effects of local anesthetics on single channel behavior of skeletal muscle calcium release channel. J Gen Physiol. 1993 Feb;101(2):207–233. doi: 10.1085/jgp.101.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Xu L., Tripathy A., Pasek D. A., Meissner G. Potential for pharmacology of ryanodine receptor/calcium release channels. Ann N Y Acad Sci. 1998 Sep 16;853:130–148. doi: 10.1111/j.1749-6632.1998.tb08262.x. [DOI] [PubMed] [Google Scholar]
  39. Zhu X., Gurrola G., Jiang M. T., Walker J. W., Valdivia H. H. Conversion of an inactive cardiac dihydropyridine receptor II-III loop segment into forms that activate skeletal ryanodine receptors. FEBS Lett. 1999 May 7;450(3):221–226. doi: 10.1016/s0014-5793(99)00496-2. [DOI] [PubMed] [Google Scholar]
  40. el-Hayek R., Antoniu B., Wang J., Hamilton S. L., Ikemoto N. Identification of calcium release-triggering and blocking regions of the II-III loop of the skeletal muscle dihydropyridine receptor. J Biol Chem. 1995 Sep 22;270(38):22116–22118. doi: 10.1074/jbc.270.38.22116. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES