c-Src Regulates the Interaction between Connexin-43 and ZO-1 in Cardiac Myocytes

Toyofuku, Toshihiko; Akamatsu, Yoshiki; Zhang, Hong; Kuzuya, Tsunehiko; Tada, Michihiko; Hori, Masatsugu

doi:10.1074/jbc.m005826200

Cited by 192 publications

(190 citation statements)

References 46 publications

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“…It has been variously proposed that ZO-1 enhances GJ assembly (Laing et al 2005), plays a role in GJ disassembly (Akoyev and Takemoto 2007), or mediates GJ internalization (Barker et al 2002;Segretain et al 2004). ZO-1 also has been implicated in the regulation of intercellular communication through Cx43 GJs (Akoyev and Takemoto 2007;Girao and Pereira 2007;Laing et al 2005;Toyofuku et al 2001;van Zeijl et al 2007). Given the predominant edge-localization of ZO-1, it is possible that many of these processes are integrated at plaque edges, with modality determined by which molecules ZO-1 actively links to (or disengages from) Cx43.…”

Section: Resultsmentioning

confidence: 99%

The Second PDZ Domain of Zonula Occludens-1 Is Dispensable for Targeting to Connexin43 Gap Junctions

Hunter

Gourdie

2008

Cell Communication & Adhesion

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Zonula occludens (ZO)-1 is emerging as a central player in the control of gap junction (GJ) dynamics. Previously the authors reported that ZO-1 localizes preferentially to the periphery of Cx43 GJs. How ZO-1 arrives at GJ edges is unknown, but this targeting might involve we established interaction between the Cx43 C-terminus and the PDZ2 domain of ZO-1. Here the show that despite blocking the canonical PDZ2-mediated interaction by fusion of GFP to the C-terminus of Cx43, ZO-1 continued to target to domains juxtaposed with the edges of GJs comprised solely of tagged Cx43. This edge-association was not abolished by deletion of PDZ2 from ZO-1, as mutant ZO-1 also targeted to the periphery of GJs composed of either tagged or untagged Cx43. Additionally, ZO-2 was found colocalized with ZO-1 at GJ edges. These data demonstrate that ZO-1 targets to GJ edges independently of several known PDZ2-mediated interactions, including ZO-1 homodimerization, heterodimerization with ZO-2, and direct ZO-1 binding to the C-terminal residues of Cx43.

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Section: Resultsmentioning

confidence: 99%

The Second PDZ Domain of Zonula Occludens-1 Is Dispensable for Targeting to Connexin43 Gap Junctions

Hunter

Gourdie

2008

Cell Communication & Adhesion

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“…Analogous to its role in tight junctions, ZO-1 was originally thought to link Cxs to the actin cytoskeleton, but now appears to be involved in the formation, assembly, distribution, turnover, and function of GJ channels (28,33,(40)(41)(42)(43). Our results indicate that ZO-1 is prominent at electrical synapses composed of Cx35.…”

Section: Discussionmentioning

confidence: 99%

“…4E was neither concentration-dependent nor reproducible. The lack of interaction of Cx35CT 15 with the PDZ2 domain did not result from a lack of instrumental sensitivity, as a peptide corresponding to the last 20 aa of the Cx43 C terminus (Cx43CT 20 ; PSSRASSRASSRPRPDDLEI), which includes the reported PDZ2 binding motif (27,33), bound with higher affinity to the PDZ2 domain of ZO-1 in a concentrationdependent manner ( Fig. 4F; one run on a chip with two levels of ligand).…”

Section: Cx35mentioning

confidence: 99%

Interaction between connexin35 and zonula occludens-1 and its potential role in the regulation of electrical synapses

Flores

Bennett

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Although regulation of chemical transmission is known to involve the interaction of receptors with scaffold proteins, little is known about the existence of protein-protein interactions in regulating gap junction-mediated electrical synapses. The scaffold protein zonulaoccludens-1 (ZO-1), a member of the MAGUK family of proteins, was reported to interact with several connexins (Cxs). We show here that ZO-1 extensively colocalizes with Cx35 at identifiable ''mixed'' (electrical and chemical) contacts on goldfish Mauthner cells, a model synapse for the study of vertebrate electrical transmission where it is possible to correlate physiological properties with molecular composition. Further, our analysis indicates that these proteins directly interact at goldfish electrical synapses. In contrast to Cx43, which interacts with ZO-1 via the PDZ2 domain, Cx35 interacts with ZO-1 via the PDZ1 domain, and this association is of lower affinity. The properties of the ZO-1/Cx35 association suggest the existence of a more dynamic relation between these two proteins, possibly including a role of ZO-1 in regulating gap junctional conductance at these highly modifiable electrical synapses. The interaction of ZO-1 with conserved regions of the C termini of Cx35/Cx36 orthologs may have a common function at electrical synapses of mammals and other vertebrates.gap junction ͉ Mauthner cell ͉ PDZ ͉ postsynaptic density-95 protein ͉ synaptic plasticity M ost electrical synaptic transmission is mediated by clusters of ion channels, known as gap junctions (GJs), that provide a low-resistance pathway between the interiors of coupled cells and permit the spread of electrical currents between them (1). Although regulation of chemical transmission is known to involve the action of multiple interacting proteins at both presynaptic and postsynaptic sites (2), little is known about the existence of protein interactions in regulating electrical synapses. Direct interactions of ligand-gated ion channels with several scaffold proteins play an essential role in the regulation of synaptic strength at chemical synapses by facilitating channel insertion, anchoring, or removal from the plasma membrane (3-9). We show here one candidate protein, zonula occludens-1 (ZO-1), for regulation at electrical synapses.Auditory afferents terminating as single large myelinated club endings (CEs) on the distal portion of the lateral dendrite of the goldfish Mauthner cells (M-cells) are identifiable ''mixed'' (electrical and chemical) synaptic terminals. These synapses constitute a valuable model for the study of vertebrate electrical transmission where structure, biochemical composition, and physiology of individual contacts are more readily characterized than at mammalian electrical synapses (10). Electrical transmission at each terminal is mediated by Ϸ100 clusters or plaques of GJ channels (11) formed by connexin35 (Cx35) (12), the fish ortholog of mammalian Cx36 (13). The junctional conductance at these synapses is dynamically regulated by activity, and both ele...

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“…The interaction of ZO-1 and connexin-43 mainly takes place at the periphery of the gap junctional plaque Zhu et al, 2005). Notably, their binding is suppressed in the presence of Src (Sorgen et al, 2004;Toyofuku et al, 2001). A number of early studies suggested that ZO-1 targets or retains connexin-43 to the ID, while others proposed that it regulates the size of gap junctions or the internalization of connexin-43 (Barker et al, 2002;Hunter et al, 2005;Rhett et al, 2011;Toyofuku et al, 1998).…”

Section: Connexin-43 Interacts With Zo-1 Caveolins and Microtubules mentioning

confidence: 99%

“…Although a complete listing of all identified kinases is beyond the scope of this chapter, we will refer to major ones, highlighting their roles during normalcy and stress. Connexin-43 is a substrate of Src tyrosine kinase, which phosphorylates Tyr-265 to disrupt its interaction with ZO-1 (discussed below, Toyfuku et al, 2001), and suppress gap junction communication in the failing heart (Giepmans et al, 2001a;Toyofuku et al, 2001). Similarly, mitogen-activated protein kinase (MAPK) phosphorylates connexin-43 at Ser-255, Ser-279 and Ser-282 to repress gap junction communication (Warn-Cramer et al, 1998;Warn-Cramer et al, 1996).…”

Section: Phosphorylation Regulates the Permeability Of Connexonsmentioning

confidence: 99%

Intercellular Connections in the Heart: The Intercalated Disc

Ackermann¹,

Hu²,

Kontrogianni‐Konstantopoulos³

2012

Cardiomyopathies - From Basic Research to Clinical Management

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c-Src Regulates the Interaction between Connexin-43 and ZO-1 in Cardiac Myocytes

Cited by 192 publications

References 46 publications

The Second PDZ Domain of Zonula Occludens-1 Is Dispensable for Targeting to Connexin43 Gap Junctions

The Second PDZ Domain of Zonula Occludens-1 Is Dispensable for Targeting to Connexin43 Gap Junctions

Interaction between connexin35 and zonula occludens-1 and its potential role in the regulation of electrical synapses

Intercellular Connections in the Heart: The Intercalated Disc

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