From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040
Over 100 years ago Sydney Ringer first showed
that extracellular Ca2+ was necessary for muscle
contractions (1). Research during the past 50 years has revealed that
intracellular Ca2+ mediates a large number of cellular
responses with the high affinity and specificity required for a
regulatory second messenger. The identification and biochemical
characterization of Ca2+-dependent signaling
pathways were stimulated by the pioneering proposal that
Ca2+ acts by binding to specific intracellular proteins,
which may be considered Ca2+ receptors (2). The class of
proteins that binds Ca2+ with high affinity and specificity
now includes hundreds of members (3). Nevertheless, a large proportion
of studies focused on calmodulin because it was recognized as a
regulator of many different target enzymes (4). Calmodulin interactions
with proteins are categorized into six distinct classes based on
Ca2+-independent and -dependent modes of
binding and regulation (5). Complementary structural features in both
calmodulin and respective target proteins allow diverse and discrete
modes of effector regulation.
Biophysical studies of Ca2+ binding to calmodulin and
Ca2+/calmodulin binding to peptide targets from
Ca2+/calmodulin-dependent protein kinases have
provided insights into how calmodulin functions (5, 6). Calmodulin has
four Ca2+-binding sites with two in a globular N-terminal
domain separated by a flexible Based upon biophysical and biochemical studies with target enzymes,
models of Ca2+/calmodulin-dependent cellular
responses have been proposed and tested, employing the integrative
powers of genetic, cell biological, and physiological approaches. Much
of our understanding of Ca2+/calmodulin regulation of
biological processes comes from the wealth of information on
calmodulin-dependent protein kinases I, II, IV, and myosin
light chain kinases, in addition to the calmodulin-dependent protein phosphatase, calcineurin.
Protein phosphatases play dynamic roles in diverse cellular processes.
Protein phosphatase IIB, or calcineurin, is a serine/threonine protein phosphatase activated by Ca2+/calmodulin and, thus,
couples Ca2+ signals to specific cellular responses via
protein dephosphorylation (10). Calcineurin was initially identified in
neuronal tissues, but it was quickly recognized that it had a broad
tissue distribution and a highly conserved structure from yeast to man.
The immunosuppressive drugs, cyclosporin A and FK506, were initially
used to discover the essential role of calcineurin in T cell activation
(11), and these pharmacological inhibitors have provided tools to
explore the roles of calcineurin in diverse
Ca2+-dependent signaling pathways (12).
Calcineurin has been implicated in a wide variety of biological
responses involving transcriptional mechanisms, and in the first
minireview in this series ("Calcium, Calcineurin, and the
Control of Transcription") Gerald R. Crabtree will review its role in
regulating transcription during development via dephosphorylation of
the NF-AT transcription complex. Ca2+ also regulates
transcription through phosphorylation of several transcription factors,
including CREB and MEF2, by a
Ca2+/calmodul-independent protein kinase cascade
involving three distinct kinases.
Ca2+/calmodulin-dependent protein kinases I and
IV have broad but overlapping substrate specificities and similar
mechanisms of activation. Both kinases are phosphorylated by a third
kinase, which enhances
Ca2+/calmodulin-dependent activity. In the
second minireview ("Defining Ca2+/CaM-dependent Protein
Kinase Cascades in Transcriptional Regulation") Ethan E. Corcoran and
Anthony R. Means will review the biochemical properties of this cascade
and its physiological role in mediating Ca2+ regulation of
specific transcriptional processes.
Another ubiquitous effector of Ca2+ signaling is the
multifunctional Ca2+/calmodulin-dependent
protein kinase II, which has broad substrate specificity with
substrates found in nuclear, cytoskeletal, and membrane compartments of
cells (13). Much of the early work focused on understanding its
biochemical properties, including the autophosphorylation mechanism
that results in the trapping of calmodulin on the kinase and conversion
of the enzyme to a Ca2+-independent form. The dynamic and
spatial aspects of autophosphorylation are an important element of
regulation, allowing it to respond to transient cellular
Ca2+ oscillations. The third minireview ("Cellular
Signaling through Multifunctional Ca2+/Calmodulin-dependent
Protein Kinase II" by Thomas R. Soderling, Bill Chang, and Debra
Brickey) will focus on the role of
Ca2+/calmodulin-dependent protein kinase II in
the neuronal synapse where its translocation and activation regulate a
number of proteins in the postsynaptic cell.
In contrast to the Ca2+/calmodulin-dependent
protein kinases and calcineurin that have broad substrate
specificities, myosin light chain kinases are dedicated protein kinases
for which the only known physiological substrate is the regulatory
light chain of myosin II. Early studies focused on its biochemical
properties, including the mechanism of activation by
Ca2+/calmodulin, with an emphasis on its role in muscle
tissues (14, 15). However, the discovery in nonmuscle cells of other
conventional myosin IIs with diverse functions such as cell spreading
and migration, cytokinesis, cell adhesion, secretion, and cytoskeletal
arrangements that affect plasma membrane ion movements has broadened
our perspective on the functional importance of this enzyme (16-18).
Recent interest has also been stimulated by its involvement in
pathophysiological processes. In the fourth minireview ("Dedicated
Myosin Light Chain Kinases with Diverse Cellular Functions") Kristine
E. Kamm and James T. Stull will review the family members of the
dedicated myosin light chain kinases and how they participate in
regulating diverse cellular functions.
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-helix from a C-terminal globular
domain containing the other two Ca2+-binding sites. In the
presence of Ca2+ each domain adopts an open conformation
exposing a hydrophobic pocket that renders calmodulin functional
for binding to target sequences. The process of complex formation
includes sequential interactions between the C-terminal hydrophobic
pocket with a hydrophobic residue in the target N-terminal
sequence followed by interactions between the N-terminal globular
domain with the C-terminal sequence of the calmodulin-binding
domain. Calmodulin thus collapses and wraps around the peptide,
resulting in the formation of a high affinity complex. The high
affinity binding of calmodulin to a target sequence is only partly
responsible for enzyme activation as surface residues on calmodulin may
subsequently interact with other areas of the enzyme (7-9).
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.
To whom correspondence should be addressed: Dept. of Physiology,
University of Texas Southwestern Medical Center, 5323 Harry Hines
Blvd., Dallas, TX 75390-9040. Tel.: 214-648-9004; Fax: 214-648-8875; E-mail: James.Stull@utsouthwestern.edu.
Published, JBC Papers in Press, November 28, 2000, DOI 10.1074/jbc.R000030200
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