THE ROLE OF CALSEQUESTRIN IN EXCITATION-CONTRACTION COUPLING AND ITS POSSIBLE CONTRIBUTION TO SKELETAL MUSCLE DISEASES

OBJECTIVE. The aim of this proposal is to define the role of skeletal Calsequestrin (sCSQ) in modulating the sarcoplasmic reticulum (SR) Ca2+ release channels (or RyRs), and investigate its possible role in myopathies such as malignant hyperthermia (MH) and central core disease (CCD). BACKGROUND. Several muscle pathologies result from alterations in intracellular Ca2+ signaling and have been associated with expression abnormalities, or mutations, of proteins involved in excitation-contraction (e-c) coupling, i.e. the mechanism that controls muscle contraction. For example, MH, a toxic response to anesthetics that has unexpectedly killed many individuals, and CCD, a myopathy that is characterized by hypotonia and proximal muscle weakness, have been associated with mutations of genes encoding for RyR1 (the skeletal Ca2+ release channel of the SR), for DHPR (the voltage sensor of e-c coupling) and even for Na2+ channels and myosin. While we know much more about the genetic origin of several of these myopathies that we did ten years ago, there are still many obscure aspects that need to be investigated. DESCRIPTION OF PROJECT. CSQ is a protein that binds Ca2+ within the SR and concentrates it in the terminal cisternae near the sites of Ca2+ release (RyRs). Furthermore, CSQ may play an active role in controlling the activity of the SR Ca2+ release channels, or RyRs. For this reason, CSQ could be involved in myopathies such as MH and CCD. To test this hypothesis we have created a transgenic mouse carrying a knockout for skeletal CSQ (sCSQ-null). Preliminary findings show that the mutation is not lethal and apparently no significant alterations are observed under standard housing conditions. However, a few mice in the sCSQ-null colony die at an early age without apparent reason. The goal of the proposal is to study muscle function and structure in these mutants to determine the effect of this mutation and to identify a possible link with known myopathies.