© 2000 American Heart Association, Inc.
Editorial |
Connections Count
Excitation-Contraction Meets Excitation-Transcription Coupling
From the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Mark E. Anderson, MD, PhD, Vanderbilt University Medical Center, Departments of Medicine and Pharmacology, 315 Medical Research Building II, Nashville, TN 37232-6300. E-mail mark.anderson{at}mcmail.vanderbilt.edu
Key Words: L-type Ca2+ channel • [Ca2+]i • nuclear pore • calmodulin kinase • adenylate cyclase
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Introduction |
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 Top Introduction References |
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It is increasingly clear that cell-signaling systems serve multiple functions. Signaling molecules that play a highly visible functional role in muscle by regulating intracellular Ca2+ ([Ca2+]i) homeostasis and contraction are also coupled to the genetic machinery of the cell and thereby shape the repertoire of expressed proteins. Our emerging understanding of excitation-contraction coupling (ECC) follows this theme (Figure
). ECC occurs when
Ca2+ entry, mostly through L-type
Ca2+ channels,1 2 activates
Ca2+ release from channels guarding the content
of [Ca2+]i stores. In
vascular smooth muscle, 2 channel types are important: ryanodine
receptors that operate by a Ca2+-induced
Ca2+ release mechanism3 and inositol
trisphosphate (IP3) receptors that are sensitized
by [Ca2+]i but open after
binding IP3.4 The situation in
cardiomyocytes seems to be somewhat simpler, as only the
ryanodine receptors have a demonstrated role in ECC. ECC is mainly
controlled by short-term signaling events to regulate the continuous
ebb and flow of activator
[Ca2+]i that is necessary
for cycling myofilament crossbridge formation. Nevertheless, the
molecular machinery of ECC also regulates the transcriptional activity
of the cell over a much longer time scale by a process termed
excitation-transcription coupling (ETC).5
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An important question in signal transduction is how ETC mechanisms in
muscle screen out the constant
[Ca2+]i fluctuations to
deliver cogent instructions to the nucleus. One answer to this question
is that transcription factors have distinct response characteristics
that may refine the message content of
[Ca2+]i
oscillations. In B lymphocytes, the transcription
regulatory proteins nuclear factor-
B, JNK, and NFAT are
differentially activated by brief Ca2+
signals of high magnitude compared with prolonged
Ca2+ signals of lower magnitude.6
Location is also important. Regulatory proteins may be anchored (by
specific binding proteins)7 or confined to distinct
intracellular domains (eg, the nucleus)8 that experience
very different Ca2+ signals than those measured
in the bulk cytoplasm. Connections are essential for success.
Ca2+ entry through L-type
Ca2+ channels seems to constitute a
"privileged" pathway that can selectively couple to the
Ca2+-binding protein calmodulin for
signaling Ca2+-dependent transcriptional events
in neurons9 or for excitation-secretion coupling in
chromaffin cells.10 These possibilities are only now
beginning to be explored in the cardiovascular
system.
To understand how we might manipulate the connections between ECC and ECT, it is necessary to know where and how these 2 systems interact. Ca2+-activated kinases and phosphatases are important linking molecules that can coordinate interactions between ECC and ETC. After activation by increased [Ca2+]i, these enzymes alter the phosphorylation state of Ca2+ regulatory protein complexes to directly modulate ECC and act on Ca2+-dependent transcription factors that "tune" ECC over a longer time frame by affecting expression of ECC regulatory proteins. This proposed linkage has important implications for disease: cardiomyopathy has been associated with disordered expression of several key Ca2+ homeostatic proteins, including the Na+-Ca2+ exchanger SR Ca2+ ATPase11 12 and numerous sarcomeric proteins.13 Expression of a constitutively active form of the Ca2+ and calmodulin-activated phosphatase calcineurin causes profound hypertrophy and dilated cardiomyopathy,14 whereas constitutive expression of calmodulin kinase (CaMK) IV results in a hypertrophic phenotype with less pronounced systolic dysfunction (Eric Olson, personal communication, November 1999). Expression of some CaMK isoforms is increased in human heart failure8 and atrial fibrillation,15 2 diseases linked to heart rate and Ca2+-dependent electrical remodeling. Electrical remodeling in heart failure is associated with action potential prolongation16 that may itself be an important stimulus for CaMK activation17 by increasing the duration of the [Ca2+]i transient.18 CaMK also participates in ECC by modulating Ca2+ entry through L-type Ca2+ channels19 and by regulating uptake20 and release of Ca2+ from intracellular stores.21 22 23 These examples may illustrate important consequences of pathophysiological ECC-ETC interactions.
The study by Cartin et al24 in this issue of Circulation Research links the phosphorylation of the cAMP response element binding (CREB) protein and consequent induction of c-fos to CaMK-dependent and Ca2+-independent signal transduction. In addition to enhancing our conceptual understanding of the ECC-ETC link in vascular smooth muscle, this study nicely highlights one important experimental issue in signaling research: the details of cellular ultrastructure matter. Cartin et al were the first to report the paradoxical effect of suppressing Ca2+ sparks in vascular smooth muscle25 that results in increased [Ca2+]i because of inactivation of a Ca2+-activated cell membrane K+ current. In contrast, the [Ca2+]i transient is virtually ablated in cardiomyocytes under conditions where sparks are eliminated. Thus, the interactions of ECC and ETC are dependent on specific cellular environments. One of the important questions that follow from the present work is the identity of the CaMK type responsible for CREB phosphorylation. Cartin et al found that both CaMK II and IV were present in vascular smooth muscle. CaMK IV is thought to be predominantly nuclear, whereas CaMK II may exist in the cytoplasm or nucleus, depending on the isoform mix of the heteromultimerized holoenzyme,26 and both types can phosphorylate CREB. The consequences of CREB phosphorylation by CaMK II may be inhibitory, because CaMK II can effectively phosphorylate a second negative regulatory site (Ser142). However, both CaMK II and IV can phosphorylate the activating site (Ser133),27 suggesting that CaMK IV may have determined c-fos levels in these experiments. Details of the probable counterregulation of CaMK-mediated CREB phosphorylation by phosphatases in vascular smooth muscle also remain to be elucidated. Finally, linkage of ECC and ETC by kinases and phosphatases offers the possibility of novel therapeutic tools to address cardiovascular disease.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (HL03727 and HL62494) and the American Heart Association Southeast Affiliate. Drs Jeffrey R. Balser (Departments of Anesthesia and Pharmacology, Vanderbilt University Medical Center), Roger J. Colbran (Department of Molecular Physiology, Vanderbilt University Medical Center), Sabina Kupershmidt (Department of Pharmacology, Vanderbilt University Medical Center), and Dan Roden (Departments of Medicine and Pharmacology, Vanderbilt University Medical Center) provided helpful comments and criticisms.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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