Critical Role of Intracellular RyR1 Calcium Release Channels in Skeletal Muscle Function and Disease

Abstract

The skeletal muscle Ca(2+) release channel, also known as ryanodine receptor type 1 (RyR1), is the largest ion channel protein known and is crucial for effective skeletal muscle contractile activation. RyR1 function is controlled by Cav1.1, a voltage gated Ca(2+) channel that works mainly as a voltage sensor for RyR1 activity during skeletal muscle contraction and is also fine-tuned by Ca(2+), several intracellular compounds (e.g., ATP), and modulatory proteins (e.g., calmodulin). Dominant and recessive mutations in RyR1, as well as acquired channel alterations, are the underlying cause of various skeletal muscle diseases. The aim of this mini review is to summarize several current aspects of RyR1 function, structure, regulation, and to describe the most common diseases caused by hereditary or acquired RyR1 malfunction.

Keywords: Ca2+ release channel; RyR1 dysfunction and disease; RyR1-related mutations; excitation-contraction coupling; ryanodine receptor type 1; sarcolemma; sarcoplasmic reticulum; skeletal muscle.

Figure 1

Muscle structure and function: from the myofiber to RyR1 Ca²⁺ release complex. (A) Morphology of skeletal muscle fibers. Top Panel: Transmitted light image of isolated muscle fibers from mouse flexor digitorum brevis via enzymatic dissociation; image was acquired using low magnification. Lower Panel: A higher magnification image of the fiber segment enclosed by a dashed rectangle. Note the characteristic striated pattern of muscle fibers, which results from highly organized array between sarcolemma, sarcoplasmic reticulum (SR), contractile elements and cytoarchitecture of the fibers. (B) Structure of the triad. In most cases the myoplasmic side of the junctional SR is closely apposed either to T-tubule or surface membrane, forming different junctions called dyads, triads, or peripheral coupling. The cartoon depicts a longitudinal section of the T-tubule axis, but a cross-section of the triad, a specialized array formed by the T-tubule and two segments of the terminal junctional SR (aka the terminal cisternae). The T-tubules are invaginations of the sarcolemma that propagate the action potential and possess the Ca_v1.1 voltage sensors that initiate the early steps of ECC. The voltage dependent Ca²⁺ channels, Cav1.1 (blue, aka DHPR), are positioned in both the T-tubule and sarcolemma. The SR Ca²⁺ release channel, RyR1 (brown), is located on the junctional domain of the SR surface, facing the T-tubules, and is also known as the junctional SR face membrane. Some RyRs may be present in adjacent parajunctional SR domains (orange). (C) Detailed architecture of the Cav1.1-RyR1 complex shown in (B). About half of the total RyR1s do not associate with Cav1.1, resulting in an alternating pattern of “free” and Cav1.1-associated RyR1s. Note: In addition to Cav1.1 and RyR1, many other proteins form part of the T-tubule- junctional SR complex (e.g., FKPB12, triadin, junctin, Casq1) and are not shown here. Panels (B,C) are based on references: (Franzini-Armstrong and Porter, ; Franzini-Armstrong and Nunzi, ; Block et al., ; Franzini-Armstrong and Jorgensen, ; Franzini-Armstrong and Kish, ; Franzini-Armstrong and Protasi, 1997).

Figure 2

Cav1.1-RyR1 complex: molecular details. Shown is a reconstruction from cryo-electron microscopy of the mammalian RyR1 at 4.8 Å illustrating the different regions. This includes the large myoplasmic segment and its multiple cavities and processes, and the SR transmembranal segment, which forms the Ca²⁺ conduction pathway (Electron microscopy data bank entry 6106, Zalk et al., 2015). The above properties allow the RyR1 to interact with multiple SR luminal and cytosolic proteins. Several 3-D structures of proteins interacting with RyR1, as well as their relative locations, are also shown. EMData bank PDB entry and references: calsequestrin-1 (Casq1) polymer (3UOM, Sanchez et al., 2012), FKBP-12 (1D6O, Burkhard et al., 2000), S100A1 (2K2F; Wright et al., 2008), calmodulin (CaM; 1CLL, Chattopadhyaya et al., 1992), Cav1.1α subunit (4MS2, Tang et al., ; Hu et al., 2015), and Cav1.1 β subunit (1T0J, Van Petegem et al., ; Hu et al., 2015); only two alpha and two beta subunits are shown. In the muscle fiber Ca_v1.1 channels are clustered in groups of four (or tetrads) in the T-tubules. Ca_v1.1 channels in the tetrad interact with the four subunits of the RyR1, one Cav1.1 per each RyR1 subunit. All structures were generated using UCSF Chimera (Pettersen et al., 2004).