Amino Acid Residues 489–503 of Dihydropyridine Receptor (DHPR) β1a Subunit Are Critical for Structural Communication between the Skeletal Muscle DHPR Complex and Type 1 Ryanodine Receptor

The β 1a 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 C-terminal end of this auxiliary subunit in the functional and structural communication between the DHPR and the Ca 2+ release channel (RyR1). Progressive truncation of the β 1a C terminus showed that deletion of amino acid residues Gln 489 to Trp 503 resulted in a loss of depolarization-induced Ca 2+ release, a severe reduction of L-type Ca 2+ currents, and a lack of tetrad formation as evaluated by freeze-fracture analysis. However, deletion of this domain did not affect expression/targeting or density ( Q max ) of the DHPR-α 1S subunit to the plasma membrane. Within this motif, triple alanine substitution of residues Leu 496 , Leu 500 , and Trp 503 , which are thought to mediate direct β 1a -RyR1 interactions, weakened EC coupling but did not replicate the truncated phenotype. Therefore, these data demonstrate that an amino acid segment encompassing sequence 489 QVQVLTSLRRNLSFW 503 of β 1a 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 the motif Leu 496 -Leu 500 -Trp 503 within the β 1a C-terminal tail plays a nonessential role in the bidirectional DHPR/RyR1 signaling that supports skeletal-type EC coupling.Dihydropyridine receptor (DHPR) β 1a subunit is essential for muscle contraction. Results Deletion of residues 489–503 in the β 1a C terminus prevents calcium signaling and DHPR tetrad formation. Conclusion β 1a C terminus is critical for structural communication with the Ca 2+ release channel. Significance The β 1a C-terminal tail is as important as the DHPR α 1S II–III loop for skeletal EC coupling.