About the Lab
Skeletal Muscle Excitation-Contraction coupling, ryanodine receptors L-type Ca2+ Channels and diseases of skeletal muscle.
The Hamilton laboratory has been studying excitation-contraction coupling in skeletal muscle and the molecular mechanisms of human diseases related to E-C coupling for more than 20 years. We began at a very molecular level studying the structure and function of the t-tubule L-type Ca2+ channel and the sarcoplasmic reticulum Ca2+ release channel. We have now expanded our studies to assess the function of these proteins in tissues and animals. We use a wide range of techniques to study these processes including protein biochemistry, molecular biology, radioligand binding, electron cryomicroscopy and angular reconstitution, reconstitution of channels into planar lipid bilayers, Ca2+ imaging and measurement of whole cell Ca2+ currents and Ca2+ transients, creation of new mouse models using knock-out, knock-in and directed expression techniques, contractile studies on isolated muscle, real time PCR, and sectioning and histochemical staining.
More recent goals of the Hamilton laboratory include the elucidation of the mechanisms underlying the disease processes of malignant hyperthermia (MH) and central core disease (CCD) and development of new therapeutic interventions. Specifically, we are using several newly developed mouse models to define how MH mutations in RyR1 produce temperature sensitive E-C coupling and Ca2+ leak that lead to MH and the destruction of mitochondria associated with CCD. The Hamilton lab created the first mouse model (a knockin mutation into RyR1) of malignant hyperthermia and has also created a mouse model of central core disease.
Above: A-resolution cryoEM structure of RyR1 channel in the closed conformation. Structure is shown in three views: view from cytoplasm, side view and view from SR lumen. The transmembrane (TM) region is shown in blue. Right panel: The transmembrane region of RyR1 is shown in a side view with the SR lumenal face up. Two opposing subunits were computationally removed. Alpha helices identified in the TM structure are annotated with cylinders.