LABORATORY OF EDUARDO RIOS AND JINGSONG ZHOU
Section of Cellular Signaling
Department of Molecular Biophysics & Physiology
Calcium signaling
is a ubiquitous mechanism linking plasma membrane events to metabolic change. Excitation-contraction (E-C) coupling, the process that translates muscle membrane depolarization to increase in intracellular [Ca2+] and contraction, is the first recognized example of Ca signaling. Our group strives to understand E-C coupling at the molecular and cellular levels. These questions transcend muscle physiology; indeed, the concepts emerging from the muscle studies find general applicability, given the widespread distribution of Ca signaling in other types of muscle, nerve cells and other tissues.
Here we describe the general aims and approaches of our research. Readers interested in current issues, please view "Research update (2007)" and "Control of Ca inside the SR"
Approaches
are cellular and molecular.
Cellular methods include recording of calcium changes "globally" (that is, averaged over the whole cell) or locally, which is done by confocal microscopic imaging. The study of local events started in cardiac muscle with the discovery of Ca2+ sparks (Cheng et al. 1993), followed in skeletal muscle with our description of sparks: Tsugorka, Ríos and Blatter. Imaging elementary events of calcium release in skeletal muscle cells. Science 1995.
While they are local, sparks were soon found to involve multiple intracellular Ca channels. The animation is an early demonstration of the involvement of many channels. It shows a record of sparks that move along channel arrays of the Z disk as they evolve. The record spans 28 ms. From Brum et al. 2000.
Newer examples of studies of calcium signals at the local level:
Launikonis et al. Depletion “skraps” and dynamic buffering inside the cellular calcium store. PNAS USA. 2006
Ríos et al. Calcium-dependent inactivation terminates calcium release in skeletal muscle of amphibians. J Gen Physiol. 2008.
The local studies are carried out in parallel with recording of global or "whole cell" signals.
An early example was important to show
species differences that can be ascribed to
variation in the molecular makeup of the signaling apparatus: Shirokova, N.,
García, J., Pizarro, G. and Ríos, E. Ca2+release from the sarcoplasmic reticulum compared in amphibian and mammalian skeletal muscle. J. Gen. Physiol, 1996. The
differences at the global level were later matched with substantial
differences at the local level (Shirokova, García and Ríos. Local Ca2+release in mammalian skeletal muscle. J. Gen. Physiol. 1998.)
The definition of processes and mechanisms is often achieved through formal quantitative modeling. In this paper we introduced the "couplon" as the functionally relevant multi-channel unit: Stern, Pizarro and Ríos. A local control model of excitation-contraction coupling in skeletal muscle. J. Gen. Physiol. 1997.
Pharmacological profiles are a more qualitative path to separation of mechanisms: González et al. The spark and its ember. Separately gated local components of Ca release in skeletal muscle. J. Gen. Physiol. 2000.
Molecular approaches include modifying the endowment of native proteins, or adding foreign ones, to then explore the functional consequences of these changes. An example: Pouvreau et al. Ca2+ sparks operated by membrane depolarization require isoform 3 ryanodine receptor channels in skeletal muscle. PNAS USA, 2007. This study demonstrated that the functional differences among species are due to the absence of a specific version of the Ca release channel (RyR3) in the muscle of mammals.
Inside the SR
A recent focus of research in the lab is the development of techniques for quantitatively imaging calcium concentration inside cellular organelles. An early success was the development of the SEER technique. Launikonis et al. Confocal imaging of [Ca2+] in cellular organelles by SEER, Shifted Excitation and Emission Ratioing of fluorescence. J Physiol, 2005. For current developments see "Control of Ca inside the SR" .
The molecular approaches and the advances in monitoring inside the SR rely on a technique (largely due to J. Vergara and M. DiFranco, Protein Expr Purif. 2006) that allows expression of virtually any protein in muscles of adult mice.
An international Symposium, to be held in 2009 in Boston, will further explore the roles of SR proteins of excitation-contraction coupling.
Advances through our work and that of other laboratories make it possible to aim for an ambitious goal, to explain the cellular function of calcium release based on the properties of individual channels and interactions among themselves as well as with other proteins.
Contact us
Ms. Lucille Vaughn
Dept. Molecular Biophysics and Physiology
Section of Cellular Signaling,
Rush University School of Medicine
1750 W. Harrison St. Suite 1279JS
Chicago, IL 60612, USA
Office: 312-942-2081
Fax: 312-942-8711
Mail to: erios@rush.edu, lvaughn@rush.edu
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