Cardiovascular Research 2006 72(1):5-6; doi:10.1016/j.cardiores.2006.07.021
Copyright © 2006, European Society of Cardiology
Atrial gap junction remodeling: Looking for lost gaps and orphaned connexins in three dimensions
René J.P. Musters*
Laboratory for Physiology (ICaR-VU), VU University Medical Center (VUMC), Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
* Tel.: +31 20 444 1749; fax: +31 20 444 8255. Email address: r.musters{at}vumc.nl
Received 19 July 2006; accepted 25 July 2006
See article by Rucker-Martin et al. [22] (pages 69–79) in this issue.
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1. Connexins and gap junction channel function in the heart
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Gap junction channels are composed of members of a multi-gene
family of proteins called connexins. These proteins are named
by the abbreviation Cx followed by the molecular weight of the
specific protein. Mammalian cardiac myocytes express Cx43, Cx45,
and Cx40, the former being the major cardiac gap junction protein,
which is expressed in atrial and ventricular myocytes as well
as in selected regions of the atrioventricular conduction system
[1,2]. Individual gap junction channels (also called connexons)
formed by multiple connexin molecules exhibit distinct unitary
conductance, pH and voltage dependence, and permeability to
ions and small molecules as well as fluorescent dyes
[3]. Regulation
of the extent to which cardiac myocytes are electrically coupled
by gap junction channels is complex and still not well understood
[4,5]. In general, it appears that cells can rapidly (within
minutes) change the number of functional channels at the cell
surface through multiple mechanisms involving mobilization of
intracellular connexin molecules to junctional plaques, internalization
of junctional channels, changes in channel open probability
and, potentially, changes in rates of connexin synthesis and
degradation. Phosphorylation of multiple serine and tyrosine
residues in the intracellular C-terminal domains has been shown
to be important in Cx43 and Cx45 assembly into gap junction
channels and in changes in channel function, intracellular translocation,
and degradation
[6]. Indeed, Cx43 can be phosphorylated on specific
serine residues by mitogen-activated protein (MAP) kinases,
protein kinases C (PKC) and A (PKA), and casein kinase I and
on tyrosine residues by v-src and c-src
[6–8]. However,
the precise signaling mechanisms responsible for changing intercellular
coupling in cardiac myocytes are incompletely understood.
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2. Gap junction remodeling and electrical uncoupling in myocardial ischemia, cardiac hypertrophy and heart failure
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Electrical uncoupling during ischemia is a complex phenomenon
that involves closure of gap junction channels and changes in
connexin phosphorylation and redistribution. Mechanisms responsible
for initiating uncoupling during earlier stages of ischemic
injury probably involve stress-activated signaling pathways
causing changes in connexin phosphorylation. For example, the
onset of uncoupling in no-flow ischemia in isolated perfused
rat hearts is associated with progressive dephosphorylation
of Cx43, accumulation of non-phosphorylated Cx43 in junctions,
and translocation of Cx43 from junctions to an intracellular
pool
[9]. Nevertheless, the precise mechanistic relationships
between channel closure, changes in phosphorylation, and intracellular
translocation remain to be established. In contrast, early compensatory
hypertrophic growth of cardiac myocytes appears to be associated
with enhanced cell–cell communication. A recent
in vitro study has shown that application of linear pulsatile stretch
to cultured neonatal ventricular myocytes for only 1 h
causes a 2-fold increase in Cx43 expression, associated with
a 30% increase in conduction velocity
[10]. Signaling pathways
involving transforming growth factor β, vascular endothelial
growth factor, and angiotensin II have been directly implicated
in stretch-induced upregulation of Cx43 expression in cultured
myocytes
[11,12]. Finally, reduced Cx43 expression in gap junctions
has been described in the hearts of patients with end-stage
heart disease of diverse etiologies, including ischemia, hypertension,
atrial fibrillation (AF), valvular abnormalities, and primary
cardiomyopathies
[13–15]. Diminished Cx43 expression in
end-stage heart disease has also been associated with selective
loss of larger gap junctions at the polar ends of cells
[16].
Although little is known about the mechanisms responsible for
changes in connexin expression and gap junction remodeling in
chronic forms of heart failure, there may be a role for c-jun
N-terminal kinase (JNK), a stress-related protein kinase activated
in response to injury caused by ischemia–reperfusion or
hemodynamic overload.
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3. Cardiac gap junction remodeling and lateral redistribution of connexins
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A recently observed remodeling feature is lateral redistribution
of gap junctions (also called "cellular lateralization"). Cellular
lateralization occurs in ventricular myocytes during healing
after myocardial infarction
[17], with right ventricular hypertrophy
secondary to pulmonary hypertension
[18], in hypertrophic cardiomyopathy
[19], and in human atria during aging
[20] and after prolonged
AF
[14]. Interestingly, cellular lateralization has also been
related to re-entrant ventricular tachycardia circuits that
develop following premature stimuli during the healing stage
of canine infarcts
[21]. Although there is an association between
inducibility of arrhythmias and cell lateralization of connexins,
it is not clear what effect the cellular redistribution of gap
junctions has on cell–cell transmission, nor what role
the remodeled lateral distribution of gap junctions plays in
altering conduction velocity at the macroscopic size scale.
Thus, knowledge of the functional consequences of cellular redistribution
of cardiac gap junctions is still quite incomplete.
In the current issue of Cardiovascular Research, Rucker-Martin et al. [22] have investigated this remodeling feature in human and rat atria, and established that it contributes to alteration of gap junctions as an early event in the development of AF. The authors used several sophisticated imaging techniques (i.e. freeze-fracture EM, TEM and 3D widefield deconvolution microscopy) to study the expression, distribution, and functionality of connexins as well as overall gap junction ultrastructure in human right atrial biopsies obtained from patients in sinus rhythm with dilated atria or in chronic AF, and in rat atria following myocardial infarction with severe structural remodeling but without AF. The authors demonstrated that connexins are redistributed (lateralized) in patients in sinus rhythm with dilated atria, and that similar alterations of connexin expression and gap junction disorganization can be reproduced in an experimental model of atrial myocardial remodeling without AF. Furthermore, regression of the atrial myopathy in rats treated with lisinopril plus spironolactone was shown to be associated with rephosphorylation and polar redistribution of Cx43. These findings suggest that structural remodeling of the atrial myocardium, especially the accompanying fibrosis, is another major factor responsible for gap junction disorganization, and warrant further investigation into the exact relationship between lateral redistribution of connexins and remodeling of the atrial interstitium.
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