Amino Acid Residues 489-503 of Dihydropyridine Receptor (DHPR) {beta}1a Subunit Are Critical for Structural Communication Between the Skeletal Muscle DHPR complex and Type-1 Ryanodine Receptor [Signal Transduction]

November 10th, 2014 by Eltit, J. M., Franzini-Armstrong, C., Perez, C. F.

The β1a subunit is a cytoplasmic component of the dihydropyridine receptor (DHPR) complex that plays an essential role in skeletal muscle excitation-contraction (EC) coupling. Here we investigate the role of the carboxyl terminal end of this auxiliary subunit in the functional and structural communication between the DHPR and the Ca2+ release channel (RyR1). Progressive truncation of the β1a C-terminus showed that deletion of amino acid residues 489Q- to -W503 resulted in loss of depolarization-induced Ca2+ release, severe reduction of L-type Ca2+ currents and lack of tetrad formation as evaluated by freeze-fracture analysis. However, deletion of this domain did not affect expression/targeting or density (Qmax) of DHPR-α1S subunit to the plasma membrane. Within this motif, triple alanine substitution of residues L496, L500 and W503, which are thought to mediate direct β1a-RyR1 interactions, weakened EC-coupling but it did not replicate the truncated phenotype. Therefore, these data demonstrate that an amino acid segment encompassing sequence 489QVQVLTSLRRNLSFW503 of β1a contains critical determinant(s) for the physical link of DHPR and RyR1, further confirming a direct correspondence between DHPR positioning and DHPR/RyR functional interactions. In addition, our data strongly suggest that motif L496-L500-W503 within the β1a C-terminal tail plays a non-essential role in the bi-directional DHPR/RyR1 signaling that supports skeletal-type EC-coupling.
  • Posted in Journal of Biological Chemistry, Publications
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