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Mechanisms of intracellular calcium release.
The Laboratory of Molecular Hermeneutics is
interested in how cells regulate their intracellular calcium concentration.
Cells use changes in calcium as a trigger for many cellular events,
including muscle contraction, hormone secretion, and cell growth. Changes
in calcium levels can be modulated in time and space by the cell to
tailor its response to the prevailing conditions. We have focused on
one aspect of this process, the release of calcium from intracellular
stores. We use electrophysiological, biochemical, and molecular techniques
combined with imaging, to study the classes of calcium release channels
known to exist inside virtually all cells: the InsP3-gated channel,
the ryanodine receptor/channel, and polycystin-2. Most cells contain
all channel types, but they vary in the relative amount of each channel.
Our goals can be divided into two general categories.
The first is to understand the basic question of how the function of
these channels is altered by binding partners and processes within the
cell. These studies will provide information on how these channels work
and will form the background for the second goal of our studies, the
investigation of disease-induced changes in calcium release channel
function. One major goal of this aspect of our studies is to understand
the changes in intracellular calcium regulation observed in cells from
patients with polycystic kidney disease. The abnormalities in calcium
regulation observed in cells from these patients may be explained by
several defects, some acting in concert. We hypothesize that abnormalities
in kidney function are consequences, at least in part, of altered calcium
release channel function. Our studies will test our hypotheses and hopefully
will lead to suitable treatment regimens.
Recent publications:
Somlo
S, Ehrlich B. Human
disease: calcium signaling in polycystic kidney disease. Curr Biol.
2001 May 1;11(9):R356-60.
Thrower,
E.C., H.S. Park, S.H. So, S.H. Yoo, and B.E. Ehrlich. Activation
of the InsP3R Ca channel by the Ca storage protein chromogranin A.
Journal of Biological Chemistry 277:15801-6 (2002)
Q-X.
Jiang, E.C. Thrower, D.W. Chester, B.E. Ehrlich, and F. J. Sigworth.
Three-dimensional
structure of type I inositol-1,4,5-triphosphate receptor at 24 ? resolution.
EMBO Journal 21:1-7 (2002).
Johenning,
F.W., M. Zochowski, S.J. Conway, A.B. Holmes, P. Koulen, and B.E. Ehrlich.
Distinct
intracellular calcium transients in neurites and somata integrate neuronal
signals. Journal of Neuruoscience 22:5344-5353 (2002).
Leite,
W.F., E.C. Thrower, W. Echevarria, P. Koulen, K. Hirata, A. Bennett,
B.E. Ehrlich, and M.H. Nathanson. Nuclear
and cytosolic calcium are regulated independently. PNAS 100: 2975-2980
(2003).
barbara.ehrlich@yale.edu
http://info.med.yale.edu/pharm/hermen
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