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Biophysics
Cell Biology and Physiology
Molecular Biology
Biophotonics
Developmental Biology
Protein Biochemistry
Biomechanics
Imaging
Structure and Ultrastructure
     


Lederer, W. Jonathan, M.D., Ph.D.
Professor and Chairman
Department of Physiology, Department of Molecular Biology & Biophysics
E-mail: jlederer@umaryland.edu


Work in the lab focuses on Ca2+ signaling in living cells. By combining confocal, two photon or wide-field microscopy imaging with whole cell patch clamp techniques, we have been able to investigate the effects of local and global [Ca2+]I on cellular function. Diverse additional tools are used as needed including flash photolysis of caged chemicals, multi-photon uncaging, single channel examination in planar lipid bilayer and by patch clamp, immunofluorescence imaging, use of cells from transgeinc and gene knockout animals, use of primary cultures and co-cultures. There are five areas of active work.

1. Cellular and Molecular Ca2+ signaling.

Local Ca2+ signals depends on the subcellualr organization of the affected cells. Ryanodine receptors (RyRs) and IP3 receptors (IP3Rs) are opened by an increase in [Ca2+]I. This local increase in [Ca2+]I may come from Ca2+ channels on the plasmalemmal membrane, that Na+/Ca2+ exchanger bringing Ca2+ into the cell, non-selective or poorly selective cation channels, or other intracellular Ca2+ release channels. Recently we have identified a new source of such activator Ca2+:Na+ channels whose selectivity is transiently modified. Specific activators and kinases modulate both the sources of Ca2+ influx and the RyRs and IP3Rs. In many cells, there are subcellular regions in which Ca2+ - conducting channels to be amplified. The RyRs and IP3Rs are intracellylar Ca2+ release channels with large conductances that are found in the sarcoplasmic reticulum and in the endoplasmic reticulum of many cells.

2. Heart Cells.

In heart cells, Ca2+ sparks reflect the Ca2+ -dependent activation of RyRs. Ca2+ sparks are the elementary events in exitation-contraction coupling. The activation of Ca2+ sparks by the L-type Ca2+ channel current (and more recently Ca2+ flux through Na+ channels) underlies normal contraction. Under normal pathalogic conditions, arrhythmais can occur due to the untowards activiation of Ca2+ sparks. In heart failure, the inadequate activation of Ca2+ sparks can explain, in part, the pathology. Current work is examining how SR Ca2+ release is activated and how it is terminated.

3. Smooth Muscle Cells.

Arterial smooth muscle contains Ca2+ -activated potassium channels and both RyRs and IP3Rs. The activation of CA2+ sparks in such smooth muscle (due to the opening of RyRs) activates the Kca channels and leads to hyperpolarization of the smooth muscle. By this means, an increase n local [Ca2+]I activates cell-wide relaxation. Much of this work was carried out using cascular smooth muscle from brain arteries. Similar results, however, occur in the coronary arteries. Current work examines how Ca2+ sparks are modulated in smooth muscle and how Ip3Rs interact with RyRs.

4. Skeletal muscle cells.

Since voltage-gated SR Ca2+ release occurs in mammalian skeletal muscle, it was surprising that we could observe Ca2+ sparks in these cells due to two processes. We observed CA2+ sparks activated directly by depolarization. In addition, we observed CA2+ sparks activated by a local increase in [Ca2+]I. Current work examines how the local [Ca2+]I signals change with development and how the developmental regulation of the transverse tubules affects Ca2+ signaling.

5. Neurons

[Ca2+]I signals in neurons appears to be more restricted in size than in muscle. Furthermore, there appears to be a larger role played by the IP3Rs. The more diverse kinds of Ca2+ channels available, the additional sources of CA2+ influx and efflux contribute to the complex regulation of local [Ca2+]I signals in neurons. Additionally, the role of local [Ca2+]I signals in influencing both pre-synaptic and post-synaptic signaling are being studied. Work has centered on an examination of DRG neurons, on cereballar Purkinje cells and on other CNS neurons that display Ca2+ -induced CA2+ -release.

Santana, L.F., Kranias, E.G., and Lederer, W.J. (1997) Calcium sparks and excitation-contraction coupling in phospholamban-deficient mouse ventricular myocytes. J. of Physiol., 503: 21-29.

Santana, L.F., Gomez, A.M. and Lederer, W.J. (1998) Ca2+ flux through promiscuous cardiac Na+ channels: Slip-mode conductance. Science, 279: 1027-1033.



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Interdisciplinary Training Program
in Muscle Biology
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