Cardiovascular Research 73 (2007) 629 – 630

www.elsevier.com/locate/cardiores

Editorial
Calmodulin and Ca 2+ /calmodulin kinases in the
heart — Physiology and pathophysiology

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Lars S. Maier a,⁎, Donald M. Bers b , Joan Heller Brown c
a
Department of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
b
Department of Physiology, Loyola University Chicago, IL, USA
c
Department of Pharmacology, UCSD, CA, USA
Received 5 January 2007; accepted 8 January 2007
Available online 12 January 2007

See reviews in this series by Maier and Bers [5] (pages 631–
640), Pitt [6] (pages 641–647), Mattiazzi et al. [7] (pages 648–
656), Anderson [8] (pages 657–666), and McKinsey [9] (pages
667–677) in this issue.
Original articles in the series are by Yurukova et al. [10]
(pages 678–688) and Vila-Petroff et al. [11] (pages 689–698),
also in this issue.
Over the last decade our view of calmodulin and Ca2+/
calmodulin kinase (CaMK) in the heart has progressed
extensively. This includes improved understanding of the
fundamental CaMKII structure, function, and physiological
roles [1,2], and more specifically how CaMKII functions in
cardiac excitation–contraction coupling [3] and pathophysio-
logical conditions such as hypertrophy and heart failure [4].
Previous reviews on these topics, including the latter in Car-
diovascular Research in 2004 that could be said to initiate the
present series, have set the backdrop for the broader series of
reviews on the burgeoning CaMKII field in the heart in this
Review Focus issue.
What drives the current interest in calmodulin and CaMK in
the heart? One factor is the potential for calmodulin and CaMK
to be intrinsically dependent on changes in intracellular Ca2+
concentration [Ca2+], which regulates not only cardiac con-
tractility but also serves as a ubiquitous second messenger.
Indeed, due to the frequent changes in [Ca2+] during systole and
diastole, the activity of calmodulin and CaMK can be regulated
on a beat-to-beat basis, can exhibit memory (or signal inte-
gration), and can participate in both very local and distant
signaling within the cell. Thus, during short-term processes
⁎ Corresponding author. Tel.: +49 551 39 9481 or 8921; fax: +49 551 39
8941 or 14370.
E-mail address: lmaier@med.uni-goettingen.de (L.S. Maier).
0008-6363/$ - see front matter © 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2007.01.005
such as excitation–contraction coupling where several ion
channels, transporters, and pumps work in concert to activate
the contractile machinery, CaM–CaMKII may help the
myocyte to fine-tune excitability and contractility, This
area is reviewed by Maier and Bers [5] and Pitt [6] in this
issue. Besides sarcolemmal voltage-gated L-type Ca2+
channels [6], sarcoplasmic reticulum (SR) Ca 2+ channels
(ryanodine receptors) regulating SR Ca 2+ release as well as
SR Ca 2+ uptake processes are subject to calmodulin and
CaMK regulation [5]. Novel data even suggests an
important role for CaMKII-dependent regulation and
phosphorylation of cardiac Na + channels [5].
In addition, it is becoming clear that this Ca2+-dependent
system may be of particular relevance under various path-
ophysiological conditions. Mattiazzi et al. [7] nicely summarize
what occurs during acidosis, where the intracellular pH drops
dramatically (e.g. during ischemic conditions such as myocar-
dial hypoperfusion in severe coronary artery disease). The
decreased myocardial contractility seen in this condition may
thus be counterbalanced by increased CaMKII-dependent
activity leading to improved SR Ca2+ uptake and, hence, at
least partial recovery of contractility. Increased CaMKII activity
may be a double-edged sword, being beneficial in some cases,
but, as clearly reviewed by Anderson [8], CaMKII can also be
directly involved in cardiac arrhythmogenic mechanisms. Data
presented from both in vitro molecular and single cell
experiments as well as in vivo whole-animal models indicate
that CaMKII can serve as a pro-arrhythmic signaling molecule
and thus represents a previously unexplored anti-arrhythmic
target distinct from the classic ion channel proteins.
Interestingly, calmodulin and CaMK may also be im-
portant for more chronic cardiac responses. Besides acute
changes in excitation–contraction coupling, excitation–
630 L.S. Maier et al. / Cardiovascular Research 73 (2007) 629–630
transcription coupling may be regulated by CaMK-depen-
dent mechanisms leading to class IIa histone deacetylase
(HDAC) phosphorylation in the nucleus and consequent
HDAC nuclear export and changes in myocyte enhancer
factor-2 (MEF2)-regulated gene expression. In his review,
McKinsey [9] suggests that protein kinase D (PKD) and
microtubule-associated kinase (MARK) are part of the
CaMK superfamily as they have catalytic domains similar
to that of CaMKII. As a consequence, PKD and MARK are
also able to phosphorylate HDAC in the nucleus, although
different HDAC isoforms may be preferred substrates for
these enzymes than for CaMKII. Thus CaMKII, along with
PKD and MARK, appears to act as HDAC kinases, leading
to HDAC derepression and inducing specific hypertrophic
responses that contribute to myocardial hypertrophy and
remodeling.
Two original articles appearing with this series further
highlight the ubiquitous role of CaMKII in pathophysiolog-
ical conditions of the heart. Yurukova et al. [10] present data
on ANP receptor-deficient mice that show cardiac hypertro-
phy and enhanced contractile performance. The authors
convincingly demonstrate that in their mouse model,
CaMKII activation and CaMKII-dependent phosphorylation
of phospholamban, not protein kinase A (PKA) actions, are
the major cause for the improved Ca2+ cycling that results in
increased cardiac contractility. In addition, Vila-Petroff et al.
[11] in their article show that CaMKII inhibition during
ischemia/reperfusion injury in Langendorff-perfused rat
hearts protects against myocyte death. One proposed mech-
anism they suggest is the decrease in SR Ca2+ release or leak
due to CaMKII inhibition.
In summary, numerous studies in the recent past have
shown that calmodulin and CaMK play important roles in the
regulation of cellular excitation–contraction coupling. A
significant role for CaMKII in cardiovascular pathophysiol-
ogy has become increasingly evident, as indicated through-
out this series of reviews and original papers. Future research
is sure to delineate a plethora of novel mechanisms by which
CaMKII and its isoforms are regulated and by which se-
lectivity in phosphorylation of its downstream substrates is
achieved, information which in turn holds promise for the
discovery of novel therapeutic approaches to treat cardio-
vascular disease.
Acknowledgments
Dr. Maier is funded by the Deutsche Forschungsge-
meinschaft (DFG) through an Emmy-Noether-grant (MA
1982/1–5) and a DFG Klinische Forschergruppe grant (MA
1982/2–1). Dr. Brown is funded by NIH grant HL80101. Dr.
Bers is funded by the National Institutes of Health (NIH)
grants HL64724 and HL80101.
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