Ryanodine receptors: structure, expression, molecular details, and function in calcium release

Abstract

Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (> 2MDa) and exist as three mammalian isoforms (RyR 1-3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

Figure 1.

Schematic figure of the interaction between RyR and various modulators. Left panel illustrates skeletal muscle and right panel shows cardiac muscle. Modulators bind to the RyR tetramer but are for simplicity only depicted on one monomer.

Figure 2.

Linear presentation of RyR primary sequence outlining known mutations associated with skeletal and cardiac muscle diseases. Diamond shaped dots represent RyR1 mutations associated with: MH (151 mutations), CCD (63 mutations), and MmD (blue, 6 mutations) or other myopathies (MP, red, 4 mutations). Circles represent RyR2 mutations associated with: CPVT (53 mutations) and ARVD2 (5 mutations). Data collected from HGMD® (database of human gene mutation data) until 2006, UniProt 2007–2009, and publication by Vukcevic et al. 2010).

Figure 3.

Cryo-EM reconstruction of RyR1 at 9.6 Å resolution. Cytoplasmic domain (A) and side view (B) of RyR1 with the different subdomains mapped by Irina Serysheva (See section “structural studies” for detailed information).