Intracellular calcium release channels: regulators of cell life and
death.
Marks, Andrew R.
Laboratory of Molecular Cardiology, Cardiovascular Institute,
Department of Medicine, Mount Sinai School of Medicine, New York,
N.Y.
APStracts 3:0461H, 1996.
Intracellular calcium release channels (CRC) on the sarcoplasmic
reticulum (SR) of striated muscle (ryanodine receptors, RyR) and on
the endoplasmic reticulum (ER) of almost all types of cells (inositol
1,4,5-trisphosphate receptors, IP3R) comprise a unique family of
molecules that are structurally and functionally distinct from all
other known ion channels. These channels play crucial roles in
calcium-mediated signaling that triggers excitation-contraction (EC)
coupling, T lymphocyte activation, fertilization, and many other
cellular functions. Three forms of RyR have been identified: RyR1
expressed predominantly in skeletal muscle, RyR2 predominantly in
cardiac muscle and RyR3 in specialized muscles, and non-muscle
tissues including the brain. RyR channels are tetramers comprised of
four subunits each with a molecular mass of 560,000 daltons. The
tetrameric structures of RyR1 and RyR2 are stabilized by a channel
associated protein known as the FK506 binding protein (FKBP). FKBP is
the cytosolic receptor for the immunosuppressant drugs FK506 and
rapamycin that inhibit the prolyl isomerase activity of FKBP and can
dissociate FKBP from RyR. Rapamycin and FK506 increase the
sensitivity of RyR to agonists such as caffeine and could be a cause
of cardiac dysfunction associated with high dose immunosuppressant
therapy by promoting leakage of calcium (Ca2+) from the SR. The role
of the prolyl-isomerase activity of FKBP in regulating RyR function
remains uncertain and several models have been proposed that could
explain how the channel is modulated by its association with FKBP.
Three forms of IP3R have been characterized by cDNA cloning, types 1,
2 and 3. Most cells have at least one form of IP3R and many express
all three types. Like RyR, the IP3R channels are tetramers comprised
of four subunits (300,000 daltons each). IP3R1 function is regulated
by at least two major cellular signaling pathways: the second
messenger IP3 activates the channel, and non-receptor protein
tyrosine kinases (e.g. Fyn) increase its open probability. During
end-stage human heart failure RyR2 mRNA and protein are downregulated
while IP3R1 is upregulated, suggesting that altered CRC levels may
contribute to defects in Ca2+ homeostasis. Cells that are deficient
in IP3R1 exhibit defective T cell receptor (TCR) signaling, thus
cannot be activated by TCR stimulation. IP3R1-deficient cells are
also resistant to induced apoptosis. Thus, RyR and IP3R play critical
roles in fundamental and diverse signaling phenomena that include EC
coupling, T cell activation, and programmed cell death.
Received 17 October 1996; accepted in final form 24 October 1996.
APS Manuscript Number H951-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 November 1996