© 1998 American Heart Association, Inc.
Editorial |
Gap Junction Proteins
Where They Live and How They Die
Correspondence to David C. Spray, PhD, Department of Neuroscience, Room 712 Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461. E-mail spray{at}aecom.yu.edu
Key Words: gap junction • connexin • proteolysis • endothelium
Gap junction channels are unique. No other channel in vertebrates provides an enclosed conduit for direct diffusional exchange of ions and small molecules between cells, and few other membrane channels have pore diameters large enough to accommodate passage of metabolites and signaling molecules with molecular weights as high as 1000 Da. Moreover, as addressed in two articles in this issue of Circulation Research, gap junctions are formed by proteins with unusually rapid turnover times1 and extremely flexible expression patterns.2
The connexin proteins that form gap junction channels are encoded by a gene family with at least 14 members in rodents. Each connexin protein has four transmembrane domains, one intracellular and two extracellular loops, and cytoplasmically located carboxyl and amino termini. Six connexin molecules, most likely arranged so that their third transmembrane domains line the channel lumen, comprise the hemichannels or connexons that are contributed by each cell of the coupled pair. Complete gap junction channels, with connexons docked across the gap of extracellular space by interactions of the extracellular loops, are commonly found clustered together, forming islands of particles or pits in freeze-fractured preparations, linearly apposed but slightly separated membranes in thin-section electron micrographs and macular regions of intercellular immunostaining with gap junction antibodies.
Remarkably, in studies first performed on rat liver in vivo3 4 and subsequently in cardiac myocytes and hepatocytes and cell lines in culture,5 6 7 8 the turnover times for connexin molecules have been found to be very short. The article by Beardslee et al1 provides direct evidence for rapid turnover dynamics of connexin43 (Cx43) in cardiac tissue, using [35S]methionine added to Langendorff-perfused rat hearts. In these experiments, the measured decay of radioactivity in immunoprecipitated Cx43 was monoexponential, which was best fit by a half-life of only 1.3 hours. This finding is significant in several respects. First, it extends in vitro observations on cultured myocytes and cell lines, in which intracellular distribution and processing of connexins might not be exactly the same as in vivo, to cardiac tissue and shows that half-life measurements on Cx43 from both preparations are similar. Second, the monoexponential decay of incorporated radioactivity in immunoprecipitated Cx43 implies the absence of a significant pool of longer-lived proteins. Finally, this finding indicates that at every interface between myocytes in the heart, the proteins forming gap junction channels are completely exchanged several times every day.
The rapid turnover of gap junction proteins raises the tantalizing possibility that remodeling of communication compartments might occur over a short period of time and also stresses the importance of understanding the intracellular trafficking events that occur during this time frame. What are the membrane folding and protein modifications that occur during the brief life of a connexin molecule, and how much of the lifetime is spent in transit compared with time functioning as an intercellular channel? Recent work by several laboratories has begun to address these issues, and although precise residence times of connexins in each of the subcellular compartments are still not well established, the general features of the connexin trafficking pathways and posttranslational processing are becoming clearer.
Connexin32 (Cx32) and Cx43 appear to be cotranslationally inserted into the endoplasmic reticulum (ER) membrane, whereas there is evidence that connexin 26 (Cx26) insertion may be cotranslational or posttranslational.6 8 9 10 Fatty acid acylation of Cx32 and Cx26 has been reported to be an early posttranslational processing event that appears to occur near the time of protein folding into the membrane9 ; whether Cx43 undergoes similar modification remains to be determined. Recent studies on Cx43 and Cx3210 11 using in vitro translation in pancreatic microsomes indicate that the initial membrane folding event is rather fragile, with a tendency for proteolytic cleavage of the first membrane–spanning domain (TM1). Whether protein chaperones or cotranslational protein modifications stabilize the burial of TM1 within the plasma membrane in whole cells also remains to be determined.
Newly synthesized connexins apparently remain as independent monomers as they begin their voyage along the secretory transport route from the ER to the Golgi apparatus. Just where it is that the connexins coalesce into connexons is unclear, although recent evidence favors a more proximal site, near the ER-Golgi transition9 10 rather than the distal trans-Golgi region as originally suggested.12 A curiosity is how the connexins can remain monomeric during their journey and why, once connexons form, they do not pair with contiguous connexons in apposed intracellular membranes. Indeed, in transfected cells overexpressing Cx43, such junctional structures are observed in intracellular membranes, and it is hypothesized that chaperone proteins, in low enough abundance to be saturable by connexin overexpression, may perform this function in normal cells.13
Movement of connexons from the distal Golgi to the junctional membrane remains mysterious. An unanswered question is whether delivery is random to anywhere on the cell surface, followed by diffusion until trapped by high affinity binding to an apposing hemichannel, or whether connexons are targeted to junctional plaques. The recent finding that a PDZ domain of the tight junction–associated protein ZO-1 binds the carboxyl terminus of Cx43 and links it to the cytoskeletal protein spectrin at intercalated disks of cardiac myocytes14 15 now allows models to be constructed and tested to determine whether scaffolds associated with gap junction proteins generate the forces that aggregate junctional channels, direct their insertion or retrieval, or juxtapose modulatory molecules at the mouths of the junctional channels.
Connexins undergo other types of posttranslational modification, including phosphorylation and ubiquitination.8 Where these modifications occur is not entirely clear, although Cx43 can be phosphorylated while in junctional plaques, and phosphorylation has been suggested to facilitate channel formation.16 Whether such modifications as phosphorylation/dephosphorylation and ubiquitin incorporation into Cx43 provide binding sites for retrieval of connexin proteins from the membrane and ultimate degradation is unknown. In the article by Beardslee et al,1 they report that selective pharmacological blockade of either lysosomal or proteasomal routes of degradation results in accumulation of junctional Cx43, indicating that both pathways normally contribute. An intriguing aspect of this study is that proteasomal inhibition caused accumulation of dephosphorylated Cx43, whereas treatment with lysosomal inhibitors increased the amount of phosphorylated Cx43 remaining in junctional membranes, suggesting that phosphorylation state might provide one signal to direct the degradation pathway. It remains to be determined whether such differential breakdown might be responsible for foreshortened half-lives reported for connexin45 mutants lacking phosphorylatable serine residues.17
Internalized annular gap junctions have been detected in dissociated cells18 19 20 and more rarely in cells maintained in culture (eg, see Reference 2121 ), and it has been suggested that one cell may degrade both the connexins in its own connexons and those phagocytosed from the neighboring cell.22 A sequential contribution of proteasomal and lysosomal degradation pathways might allow such internalization and gap junction breakdown. Consistent with such a possibility, Laing et al7 reported that in Chinese hamster ovary and heart-derived BWEM cells, Cx43 remained at the surface when the proteasome was inhibited but appeared in intracellular vesicles when the proteasome pathway was blocked.
The rapid turnover dynamics of gap junction channels implies that gap junction–mediated circuitry in tissues might be a dynamic process that responds to local demands. The first example of a tissue in which gap junction expression was shown to undergo rapid changes was the pregnant myometrium,23 in which Cx43 expression is now known to be transcriptionally upregulated at the time of labor,24 presumably acting to coordinate and thereby intensify the contractions of the uterus.
The vessel wall is an organ that undergoes both
physiological and pathological changes in response
to mechanical stresses and on exposure to hormonal stimuli. Vascular
tissue consists of two communication compartments: smooth muscle, which
predominantly expresses Cx43 (eg, see Reference 2525 ), and
endothelial cells, which Gabriels and
Paul2 show, in undisturbed aorta, express
predominantly connexin40, somewhat less Cx37, and little or no Cx43. In
culture, regulation of connexin expression by vascular smooth muscle
and endothelial cells has been evaluated with regard to
a variety of stimuli. For example, smooth muscle cells were recently
shown to respond to 20% static stretch with upregulation of Cx43 and
its mRNA within hours after application.26
Cultured endothelial cells have been shown to
upregulate Cx43 in response to wounding,27 28
application of shear stress,26 and after
treatment with transforming growth factor-ß29
and basic fibroblast growth factor,30 whereas
expression of Cx43 has been reported to decrease in response to
epidermal growth factor31 and tumor necrosis
factor-
.32 It is interesting that in the few
studies that have either measured transcription directly or evaluated
mRNA stability through treatment with cycloheximide, the
endothelial changes have been ascribed to altered mRNA
stability (eg, see References 27, 28, and 3327 28 33 ), whereas the changes in
smooth muscle have been shown to be
transcriptional.26
Comparably fewer in vivo studies have been performed to evaluate effects of vascular manipulations on connexin expression, although the findings in arterial smooth muscle cells have been striking: Cx43 expression was shown to be increased in several hypertensive models34 35 and after balloon injury,36 whereas reduced Cx43 expression resulted from hypercholesterolemia-induced atherosclerosis.37
Gabriels and Paul2 report that Cx43 is virtually absent in most regions of rodent aortic endothelium, except at sites in which branching or flow division is expected to create high turbulence, and that Cx43 expression is reciprocally related to that of Cx37. These observations may explain in part the anatomical finding that the shapes of the gap junctions arrays connecting endothelial cells in regions of vascular turbulence are different than in regions with laminar flow,38 39 and the involvement of a shear-stress induced transduction mechanism might also relate to the reported high Cx43 expression in cardiac tissue below the mitral valve.40
Gabriels and Paul2 additionally report that Cx43 expression is dramatically induced in the coarcted region at 8 days after application of ligation or a silicone cuff. This is a remarkable finding that suggests a mechanism by which myoendothelial communication might be either established or intensified at regions of altered flow. Likely consequences of such changes in connexin expression might include altered vasomotor tone or vascular reactivity as a compensation or maladaptation to such injury.
The rapid dynamics of gap junction turnover and the plasticity of gap junction expression in response to various stimuli offer the possibility for remodeling of the intercellular circuits both within and between communication compartments in the cardiovascular system. In the heart, such remodeling could exaggerate conduction discontinuities due to tissue anisotropy and thus be arrhythmogenic,41 and in the vessel wall, such altered expression may allow intercompartmental signaling that is otherwise forbidden by the lack of heterotypic junction formation by the connexins normally expressed by smooth muscle and endothelial cells.42 The next step to follow in understanding the remodeling of gap junction–mediated circuits of intercellular signaling will require the identification of cis-acting elements and trans-acting factors responsible for the altered expression of the connexin genes in response to environmental stimuli. Although surprisingly few studies thus far have addressed these control mechanisms (eg, see Reference 2424 ), reports such as that of Gabriels and Paul2 will likely stimulate additional studies, leading not only to increased understanding of connexin gene regulation but also to strategies by which expression patterns might be therapeutically manipulated.
Acknowledgments
Research in the author's laboratory is currently funded by grants from the National Institutes of Health and the Muscular Dystrophy Association. The author gratefully acknowledges conversations with Dr Elliot L. Hertzberg over the past decade that have shaped his understanding of the biochemical nature of gap junction polypeptides.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
References
1.
Beardslee MA, Laing JG, Beyer EC, Saffitz JE.
Rapid turnover of connexin43 in the adult rat heart. Circ
Res. 1998;83:629–635.
2.
Gabriels JE, Paul DL. Connexin43 is highly localized
to sites of disturbed flow in rat aortic endothelium
but connexin37 and connexin40 are more uniformly distributed.
Circ Res. 1998;83:636–643.
3. Yancey SB, Nicholson BJ, Revel JP. The dynamic state of liver gap junctions. J Supramol Struct Cell Biochem. 1981;16:221–232.[Medline] [Order article via Infotrieve]
4.
Fallon RF, Goodenough DA. Five-hour half-life of mouse
liver gap-junction protein. J Cell Biol. 1981;90:521–526.
5. Laird DW, Puranam KL, Revel JP. Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem J. 1991;273(pt 1):67–72.
6. Willecke K, Traub O, Look J, Stutenkemper R, Dermietzel R. Different protein components contribute to the structure and function of hepatic gap junctions. In: Hertzberg EL, Johnson RG, eds. Gap Junctions. New York, NY: AR Liss; 1988:41–52.
7. Laing JG, Tadros PN, Westphale EM, Beyer EC. Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp Cell Res. 1997;236:482–492.[Medline] [Order article via Infotrieve]
8.
Laing JG, Beyer EC The gap junction protein connexin43
is degraded via the ubiquitin proteasome pathway. J Biol
Chem. 1995;270:26399–26403.
9. Diez JA, Ahmad S, Evans WH. Biogenesis of liver gap junctions. In: Werner R, ed. Gap Junctions. Burke, Va: IOS Press; 1998:130–134.
10.
Falk MM, Kumar NM, Gilula NB. Membrane insertion of gap
junction connexins: polytopic channel forming membrane proteins.
J Cell Biol. 1994;127:343–355.
11.
Falk MM, Gilula NB. Connexin membrane protein
biosynthesis is influenced by polypeptide positioning within the
translocon and signal peptidase access. J Biol Chem. 1998;273:7856–7864.
12. Musil LS, Goodenough DA. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell. 1993;74:1065–1077.[Medline] [Order article via Infotrieve]
13. Kumar NM, Friend DS, Gilula NB. Synthesis, and assembly of human beta 1 gap junctions in BHK cells by DNA transfection with the human ß1 cDNA. J Cell Sci. 1995;108(pt 12):3725–3734.
14.
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.
15. Giepmans BNG, Moolenaar WH. The gap junction protein connexin43 interactions with the second PDZ domain of the zona occludens-1 protein. Curr Biol. 1998;8:931–934.[Medline] [Order article via Infotrieve]
16.
Musil LS, Goodenough DA. Biochemical analysis
of connexin43 intracellular transport, phosphorylation,
and assembly into gap junctional plaques. J Cell Biol. 1991;115:1357–1374.
17. Hertlein B, Butterweck A, Haubrich S, Willecke K, Traub O. Phosphorylated carboxy terminal serine residues stabilize the mouse gap junction protein connexin45 against degradation. J Membr Biol. 1998;162:247–257.[Medline] [Order article via Infotrieve]
18.
Mazet F, Wittenberg BA, Spray DC. Fate of intercellular
junctions in isolated adult rat cardiac cells. Circ Res. 1985;56:195–204.
19.
Larsen WJ, Tung HN, Murray SA, Swenson CA, Larsen
W. Evidence for the participation of actin microfilaments and bristle
coats in the internalization of gap junction membrane. J
Cell Biol. 1979;83:576–587.
20.
Severs NJ, Shovel KS, Slade AM, Powell T, Twist VW,
Green CR. Fate of gap junctions in isolated adult mammalian
cardiomyocytes. Circ Res. 1989;65:22–42.
21. Spray DC, Moreno AP, Kessler JA, Dermietzel R. Characterization of gap junctions between cultured leptomeningeal cells. Brain Res. 1991;568:1–14.[Medline] [Order article via Infotrieve]
22. Laird DW. The life cycle of a connexin: gap junction formation, removal, and degradation. J Bioenerg Biomembr. 1996;28:311–318.[Medline] [Order article via Infotrieve]
23.
Garfield RE, Sims SM, Kannan MS, Daniel EE. Possible
role of gap junctions in activation of myometrium during parturition.
Am J Physiol. 1978;235:C168–C179.
24.
Chen ZQ, Lefebvre D, Bai XH, Reaume A, Rossant J, Lye
SJ. Identification of two regulatory elements within the promoter
region of the mouse connexin43 gene. J Biol Chem. 1995;270:3863–3868.
25.
Christ GJ, Spray DC, el-Sabban M, Moore LK, Brink PR.
Gap junctions in vascular tissues. Evaluating the role of intercellular
communication in the modulation of vasomotor tone. Circ Res. 1996;79:631–646.
26.
Cowan DB, Lye SJ, Langille BL. Regulation of vascular
connexin43 gene expression by mechanical loads. Circ Res. 1998;82:786–793.
27. Pepper MS, Spray DC, Chanson M, Montesano R, Orci L, Meda P. Junctional communication is induced in migrating capillary endothelial cells. J Cell Biol. 1989;109(6 pt 1):3027–3038.
28. Pepper MS, Montesano R, el Aoumari A, Gros D, Orci L, Meda P. Coupling and connexin43 expression in microvascular and large vessel endothelial cells. Am J Physiol. 1992;262(5 pt 1):C1246–C1257.
29. Larson DM, Wrobleski MJ, Sagar GD, Westphale EM, Beyer EC. Differential regulation of connexin43 and connexin37 in endothelial cells by cell density, growth, and TGF-ß1. Am J Physiol. 1997;272(2 pt 1):C405–C415.
30. Pepper MS, Meda P. Basic fibroblast growth factor increases junctional communication and connexin43 expression in microvascular endothelial cells. J Cell Physiol. 1992;153:196–205.[Medline] [Order article via Infotrieve]
31. Xie HQ, Hu VW. Modulation of gap junctions in senescent endothelial cells. Exp Cell Res. 1994;214:172–176.[Medline] [Order article via Infotrieve]
32. van Rijen HV, van Kempen MJ, Postma S, Jongsma HJ. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine. 1998;10:258–264.[Medline] [Order article via Infotrieve]
33.
Kosaki K, Ando J, Korenaga R, Kurokawa T, Kamiya A.
Fluid shear stress increases the production of
granulocyte-macrophage colony-stimulating factor by
endothelial cells via mRNA stabilization. Circ
Res. 1998;82:794–802.
34.
Watts SW, Webb RC. Vascular gap junctional
communication is increased in mineralocorticoid-salt hypertension.
Hypertension. 1996;28:888–893.
35. Haefliger JA, Castillo E, Waeber G, Aubert JF, Nicod P, Waeber B, Meda P. Hypertension differentially affects the expression of the gap junction protein connexin43 in cardiac myocytes and aortic smooth muscle cells. Adv Exp Med Biol. 1997;432:71–82.[Medline] [Order article via Infotrieve]
36.
Yeh HI, Lupu F, Dupont E, Severs NJ. Upregulation of
connexin43 gap junctions between smooth muscle cells after balloon
catheter injury in the rat carotid artery. Arterioscler Thromb
Vasc Biol. 1997;17:3174–3184.
37. Polacek D, Bech F, McKinsey JF, Davies PF. Connexin43 gene expression in the rabbit arterial wall: effects of hypercholesterolemia, balloon injury and their combination. J Vasc Res. 1997;34:19–30.[Medline] [Order article via Infotrieve]
38. Huttner I, Costabella PM, De Chastonay C, Gabbiani G. Volume, surface, and junctions of rat aortic endothelium during experimental hypertension: a morphometric and freeze fracture study. Lab Invest. 1982;46:489–504.[Medline] [Order article via Infotrieve]
39. Okano M, Yoshida Y. Junction complexes of endothelial cells in atherosclerosis-prone and atherosclerosis-resistant regions on flow dividers of brachiocephalic bifurcations in the rabbit aorta. Biorheology. 1994;31:155–161.[Medline] [Order article via Infotrieve]
40.
Yeh HI, Dupont E, Coppen S, Rothery S, Severs NJ. Gap
junction localization and connexin expression in cytochemically
identified endothelial cells of arterial
tissue. J Histochem Cytochem. 1997;45:539–550.
41.
Spach MS, Heidlage JF. The stochastic nature of cardiac
propagation at a microscopic level. Electrical description of
myocardial architecture and its application to conduction. Circ
Res. 1995;76:366–380.
42. Bruzzone R, Haefliger JA, Gimlich RL, Paul DL. Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins. Mol Biol Cell. 1993;4:7–20.[Abstract]
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