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Connexin Diversity
Discriminating the Message
Mario Delmar
I
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gap junction would be different depending on the type of
connexin that is present.
Adding to the complexity is the fact that many cells express
more than one connexin isotype. Atrial myocytes, for example,
express both Cx40 and Cx43, which oligomerize into the same
hemichannel.8 In other words, atrial connexons may be heteromeric, with anywhere between 1 and 5 subunits being of one
connexin (eg, Cx40) and the rest from the alternative isotype
(Cx43). The question then is whether, in the case of a gap
junction channel made out of two different connexins, the
properties of the channel are dictated by the dominant behavior
of one subunit or by the sum of the individual properties of each
connexin in the complex.
The elegant studies of Valiunas et al,9 published in this issue
of Circulation Research, bring us a step closer to understanding
the functional consequences of connexin diversity. These authors have combined two techniques previously used independently to study gap junctions: patch clamp and dye transfer.
Through a series of simple calculations, the authors estimate the
number of Lucifer yellow molecules that traverse a gap junction
channel depending on the connexin isotype that is present: Cx40,
Cx43, or a combination of both. The findings are clear: Lucifer
yellow passes with much more ease through a Cx43 channel
than a Cx40 channel. Indeed, whereas 1351 molecules of Lucifer
yellow can move through a Cx43 channel in one second, only
272 molecules pass when the gap junction is formed by Cx40.
Comparing the ratio of potassium to Lucifer yellow permeability
gives a similar result: the ratio is more than an order of
magnitude higher in the case of Cx43. Interestingly, the numbers
for heteromeric Cx40/Cx43 channels fall in between those
obtained for the homomeric pairs. These data convincingly
support the hypothesis that the ability of a molecule to navigate
a gap junction is a function of the molecular composition of that
particular channel. The findings are as robust as they are
significant. It is tempting to speculate, for example, that variations in connexin expression within a tissue may be a key
component of any remodeling process. A case in point may be
that of atrial fibrillation, where it has been shown that the ratio
of atrial Cx40/Cx43 expression is regionally modified.10 Could
that be translated into a different type of intercellular message
that may differentially regulate myocyte gene expression and
control cardiac remodeling? In general, the results of this study
suggest that the diversity of connexins translates into a diverse
set of filters that can be placed between cells to control the flux
of molecular information as it is proper to that particular cell
group, under a particular set of conditions.
Although the nature of the molecules still remains to be
determined, this study improves our understanding of the properties that are relevant for a molecule to move (or not) through
a cardiac connexin channel. The results also support previous
n cardiac electrophysiology, gap junctions are often conceptualized as passive resistors that allow for electrical charge to
move between cells. From that standpoint, gap junctions
seem like rigid structures that sit idle between cells as small ions
traverse across. Yet, although the importance of gap junctions in
electrical synchronization is not questioned, it is generally
accepted that these structures are more than electrical elements.
Indeed, gap junctions are highly regulable molecular complexes
present in the vast majority of cells in the body, including many
cell types that are electrically nonexcitable. In addition to
allowing the passage of ions, gap junctions allow the passage of
small molecules as well. Hence, gap junctions provide not only
electrical coupling to excitable cells but also metabolic coupling
to all cell types where they are present.1 Yet, although the nature
of the message that carries electrical information is rather well
understood (ions carrying charge), the nature of the molecule(s)
providing metabolic coupling is mostly unknown. The answer to
the obvious question remains elusive: what goes through gap
junctions in living cells?
The answer to this question is complicated by the fact that not
all gap junctions are exactly the same. Gap junctions are formed
by the oligomerization of a protein called connexin (Figure). Six
connexin subunits noncovalently bind to form a hemichannel (or
connexon); two connexons, one provided by each cell, dock
their extracellular domains and open a hydrophilic pore into the
neighboring cytoplasmic spaces, forming a gap junction channel. Twenty connexins have been identified in the human
genome.2 Each connexin forms a channel with a signature
unitary conductance and voltage dependence.1 Not all connexins
act as substrates for the same kinases, and only a few are known
to associate with either scaffolding proteins,3 microtubules,4 or
other intracellular proteins.5 As such, a gap junction channel
formed by one connexin isotype may function quite differently
from another, built by a different isotype. In fact, genetic
manipulation studies show that connexins are not interchangeable. Indeed, malformations caused by the absence of one
connexin are not prevented when the missing connexin is
substituted by a different isotype.6,7 Given that individual connexins seem to have such a strong identity, it is reasonable to
speculate that the molecular messages that can traverse across a
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY.
Correspondence to Mario Delmar, MD, PhD, Department of Pharmacology, SUNY Upstate Medical University, 766 Irving Ave, Syracuse, NY
13210. E-mail [email protected]
(Circ Res. 2002;91:85-86.)
© 2002 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
DOI: 10.1161/01.RES.0000028342.56448.9F
85
86
Circulation Research
July 26, 2002
Connexins are the protein subunits that
form gap junctions. Six connexins oligomerize to form a connexon (or
hemichannel). Two connexons, one provided by each cell, dock in the extracellular space to form a gap junction channel. These channels cluster into gap
junction plaques, which are found at the
site of cell-cell apposition. In the case of
cardiac myocytes, gap junctions are
mostly found at the intercalated disk,
where they control the passage of electrical and molecular information between
cells.
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evidence indicating that, at least in the case of Cx40 and Cx43,
a mixed channel is not dominated by one isotype. Instead,
properties are added (either linearly or not11,12) to bring about a
functional unit with unique characteristics. This democratic
organization brings to the system enormous flexibility (and
complexity), as separate individuals keep their identity but, at the
same time, integrate into a unified structure to preserve the
function of the cell.
Connexin is not the only family of channel proteins that is
composed of multiple isotypes. Yet, because of the peculiarities
of the channel, connexins have been actively studied to determine what molecules, other than ions, move through, and which
functions (other than the one relevant to electrophysiology) they
cover. The data presented in this study and in others (see
Reference 1 for review) clearly show that connexin diversity
carries multiple functional implications, many of them unrelated
to the electrical behavior of the organ. One must wonder if this
is a fact exclusive to the connexin family. Take for example the
potassium channels. Numerous integral membrane proteins have
the ability to form a hydrophilic, potassium selective pore. But is
that their only function? Could they also have a different role in
cell homeostasis, maybe through their association with other
intracellular proteins and/or extracellular molecules? Could that
be a partial explanation for the large diversity of potassium
channel-forming genes?
In summary, the study by Valiunas et al9 represents a very
valuable contribution to the gap junction field and has implications for other ion channels as well. Their data emphasize the
fact that connexins may act as selectivity filters for molecular
information, and that the composition of such filters can be
modulated by the combination of individual subunits in a
somewhat democratic fashion. The big questions are still out-
standing. But this study moves us one significant step closer to
the long-sought answers.
References
1. Harris AL. Emerging issues of connexin channels: biophysics fills the
gap. Q Rev Biophys. 2001;34:325– 472.
2. Willecke K, Elberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M,
Deutsch U, Sohl G. Structural and functional diversity of connexin genes in
the mouse and human genome. Biol Chem. 2002;383:725–737.
3. Toyofuku T, Yabuki M, Otsu K, Kuzuya T, Hori M, Tada M. Direct
association of the gap junction protein connexin-43 with ZO-1 in cardiac
myocytes. J Biol Chem. 1998;273:12725–12731.
4. Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, Falk MM,
Moolenaar WH. Gap junction protein connexin-43 interacts directly with
microtubules. Curr Biol. 2001;11:1364–1368.
5. Giepmans BN, Hengeveld T, Postma FR, Moolenaar WH. Interaction of
c-Src with gap junction protein connexin-43: role in the regulation of cell-cell
communication. J Biol Chem. 2001;276:8544–8549.
6. Plum A, Hallas G, Magin T, Dombrowski F, Hagendorff A, Schumacher B,
Wolpert C, Kim J, Lamers WH, Evert M, Meda P, Traub O, Willecke K.
Unique and shared functions of different connexins in mice. Curr Biol.
2000;10:1083–1091.
7. White TW. Unique and redundant connexin contributions to lens development. Science. 2002;295:319–320.
8. Elenes S, Rubart M, Moreno AP. Junctional communication between isolated
pairs of canine atrial cells is mediated by homogeneous and heterogeneous
gap junction channels. J Cardiovasc Electrophysiol. 1999;10:990–1004.
9. Valiunas V, Beyer EC, Brink PR. Cardiac gap junction channels show
quantitative differences in selectivity. Circ Res. 2002;91:104–111.
10. van der Velden HM, Ausma J, Rook MB, Hellemons AJ, van Veen TA,
Allessie MA, Jongsma HJ. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res. 2000;46:476–486.
11. Gu H, Ek-Vitorin JF, Taffet SM, Delmar M. Coexpression of connexins 40
and 43 enhances the pH sensitivity of gap junctions: a model for synergistic
interactions among connexins. Circ Res. 2000;86:e98–e103.
12. He DS, Burt JM. Mechanism and selectivity of the effects of halothane on
gap junction channel function. Circ Res. 2000;86:e104–e109.
KEY WORDS: connexin
䡲
gap junctions
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ion channels
Connexin Diversity: Discriminating the Message
Mario Delmar
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Circ Res. 2002;91:85-86
doi: 10.1161/01.RES.0000028342.56448.9F
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