Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation–contraction coupling

In skeletal muscle tissue, an intriguing mechanical coupling exists between two ion channels from different membranes: the L-type voltage-gated calcium channel (Ca V 1.1), located in the plasma membrane, and ryanodine receptor 1 (RyR1) located in the sarcoplasmic reticulum membrane. Excitable cells rely on Ca v s to initiate Ca 2+ entry in response to action potentials. RyRs can amplify this signal by releasing Ca 2+ from internal stores. Although this process can be mediated through Ca 2+ as a messenger, an overwhelming amount of evidence suggests that RyR1 has recruited Ca V 1.1 directly as its voltage sensor. The exact mechanisms that underlie this coupling have been enigmatic, but a recent wave of reports have illuminated the coupling protein STAC3 as a critical player. Without STAC3, the mechanical coupling between Ca v 1.1 and RyR1 is lost, and muscles fail to contract. Various sequence variants of this protein have been linked to congenital myopathy. Other STAC isoforms are expressed in the brain and may serve as regulators of L-type Ca V s. Despite the short length of STACs, several points of contacts have been proposed between them and Ca V s. However, it is currently unclear whether STAC3 also forms direct interactions with RyR1, and whether this modulates RyR1 function. In this review, we discuss the 3D architecture of STAC proteins, the biochemical evidence for their interactions, the relevance of these connections for functional modulation, and their involvement in myopathy.