STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor

• Published in: Journal of cellular physiology Vol. 233; no. 12; pp. 9045 - 9051
• Main Authors: Campiglio, Marta, Kaplan, Mehmet M., Flucher, Bernhard E.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-12-2018; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Calcium - metabolism; Calcium channels (voltage-gated); Calcium Channels, L-Type - genetics; Calcium release channels; Calcium Signaling - genetics; Contraction; Coupling; DHPR; Dihydropyridine; Excitation Contraction Coupling - genetics; Excitation Contraction Coupling - physiology; Humans; Mice; Muscle contraction; Muscle Fibers, Skeletal; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Muscles; Muscular Diseases - genetics; Muscular Diseases - physiopathology; Musculoskeletal system; Myopathy; Myotubes; Nerve Tissue Proteins - genetics; Proteins; Rapid Communication; Rapid Communications; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine receptors; RyR1; Skeletal muscle; skeletal muscle excitation‐contraction coupling; STAC3; STAC3; RyR1; skeletal muscle excitation-contraction coupling; DHPR
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26767

Excitation‐contraction (EC) coupling in skeletal muscles operates through a physical interaction between the dihydropyridine receptor (DHPR), acting as a voltage sensor, and the ryanodine receptor (RyR1), acting as a calcium release channel. Recently, the adaptor protein SH3 and cysteine‐rich containing protein 3 (STAC3) has been identified as a myopathy disease gene and as an additional essential EC coupling component. STAC3 interacts with DHPR sequences including the critical EC coupling domain and has been proposed to function in linking the DHPR and RyR1. However, we and others demonstrated that incorporation of recombinant STAC3 into skeletal muscle triads critically depends only on the DHPR but not the RyR1. On the contrary, here, we provide evidence that endogenous STAC3 incorporates into triads in the absence of the DHPR in myotubes and muscle fibers of dysgenic mice. This finding demonstrates that STAC3 interacts with additional triad proteins and is consistent with its proposed role in directly or indirectly linking the DHPR with the RyR1.
STAC3 has been demonstrated to establish two discrete interactions with the DHPR: its C1 domain interacts with the IQ domain in the C‐terminus, and the SH3‐1 domain interacts with the IPR motif in the II–III loop of the DHPR. Here, we provide evidence of a third, hitherto unidentified, interaction, which anchors STAC3 in the triad junctions independent of the DHPR. Because of the crucial role of STAC3 in excitation‐contraction coupling and because no additional proteins are necessary to restore voltage‐induced calcium release in heterologous cells, STAC3 may thus directly couple the DHPR with the RyR1.