Luminal loop of the ryanodine receptor: A pore-forming segment?

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Abstract
In this issue of the Proceedings , Lynch et al. (1) report a new mutation I4898T in the skeletal muscle Ca2+ release channel/ryanodine receptor (RyR1). The mutation disrupts Ca2+ release channel function, causing severe alterations in muscle structure and function. Ryanodine receptors (RyRs) are Ca2+ channels that control intracellular Ca2+ levels by releasing Ca2+ from the sarco/endoplasmic reticulum (SR), an intracellular Ca2+ storage compartment. Mammalian tissues express three closely related RyR isoforms encoded by separate genes. All three isoforms are found in a variety of tissues, with RyR1 and RyR2 being the primary isoform in skeletal and cardiac muscle, respectively, and RyR3 being found in diaphragm, slow twitch skeletal muscles, and other tissues at low levels (2, 3). Release of Ca2+ ions from skeletal muscle SR leads to muscle contraction through complex mechanisms. One of the primary players is RyR1, a large, ligand gated ion channel in specialized junctional areas of the SR (4). RyR1 consists of four large subunits, each with a molecular mass of 565 kDa, ≈5,000 aa, and four small 12-kDa FK506 binding proteins. RyR1 mediates the release of Ca2+ from the SR lumen in response to an action potential (5–7). In skeletal muscle, Ca2+ release is triggered by direct activation of RyR1 by the dihydropyridine receptor, a voltage-sensing calcium channel in the surface membrane (8). Many endogenous and exogenous effectors contribute to RyR1 regulation (5–7). RyR1 is partially activated by Ca2+ binding to high-affinity, Ca2+-specific sites and by Ca2+ and Mg2+ binding to low-affinity, less selective sites, giving rise to the characteristic Ca2+ dependence of channel activity illustrated in Fig. 1. Other endogenous molecules and pathways that modulate RyR1 function include adenine nucleotides, …