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© The Rockefeller University Press, 0021-9525/1998//831 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 831-842

Role of Ryanodine Receptors in the Assembly of Calcium Release Units in Skeletal Muscle

Feliciano Protasi^*,, Clara Franzini-Armstrong^*, and Paul D. Allen^,

^* Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6058; Department of Cardiology, Laboratory of Molecular Cardiology, Children's Hospital, Boston, Massachusetts 02115; and Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115

Abstract. In muscle cells, excitation–contraction (e–c) coupling is mediated by "calcium release units," junctions between the sarcoplasmic reticulum (SR) and exterior membranes. Two proteins, which face each other, are known to functionally interact in those structures: the ryanodine receptors (RyRs), or SR calcium release channels, and the dihydropyridine receptors (DHPRs), or L-type calcium channels of exterior membranes. In skeletal muscle, DHPRs form tetrads, groups of four receptors, and tetrads are organized in arrays that face arrays of feet (or RyRs). Triadin is a protein of the SR located at the SR–exterior membrane junctions, whose role is not known. We have structurally characterized calcium release units in a skeletal muscle cell line (1B5) lacking Ry₁R. Using immunohistochemistry and freeze-fracture electron microscopy, we find that DHPR and triadin are clustered in foci in differentiating 1B5 cells. Thin section electron microscopy reveals numerous SR–exterior membrane junctions lacking foot structures (dyspedic). These results suggest that components other than Ry₁Rs are responsible for targeting DHPRs and triadin to junctional regions. However, DHPRs in 1B5 cells are not grouped into tetrads as in normal skeletal muscle cells suggesting that anchoring to Ry₁Rs is necessary for positioning DHPRs into ordered arrays of tetrads. This hypothesis is confirmed by finding a "restoration of tetrads" in junctional domains of surface membranes after transfection of 1B5 cells with cDNA encoding for Ry₁R.

This work was supported by National Institutes of Health grants R01 HL48093 to the Pennsylvania Muscle Institute (to C. Franzini-Armstrong), and R01AR43140 (to P.D. Allen), and by a grant from The Muscular Dystrophy Association (to P.D. Allen).

Address all correspondence to Dr. Feliciano Protasi, Department of Anesthesia Research, Brigham and Women's Hospital, 120 Shattuck Street, Boston, MA 02115. Tel.: (617) 278-0597. Fax: (617) 732-6927. E-mail: protasi{at}zeus.bwh.harvard.edu

1. Abbreviations used in this paper: 1-DHPR, -1 subunit of L-type voltage-dependent Ca²⁺ channel dihidryopyridine receptor; e-c, excitation contraction; ES, embryonic stem; HIHS, heat-inactivated horse serum; RyR, ryanodine receptor; Ry₁R, Ry₂R, and Ry₃R, skeletal isoform of ryanodine receptor, cardiac isoform of ryanodine receptor, and brain isoform of ryanodine receptor; SCID, severly compromised immunodeficient; SR, sarcoplasmic reticulum; T, transverse.

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