Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions.

Kwak, Brenda R.; Hermans, M. M. P.; Jonge, Hugo R. de; Lohmann, Suzanne M.; Jongsma, Habo J.; Chanson, Marc

doi:10.1091/mbc.6.12.1707

Cited by 161 publications

(108 citation statements)

References 54 publications

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“…Phosphorylation could have a direct effect on channel properties of Cx35/36 gap junctions, as has been seen for a number of other connexin channels. For example, Cx43 channels expressed in SkHep1 cells show a reversible shift from a 90-100 pS main state to a 60-70 pS subconductance state with activation of PKC (Moreno et al, 1994;Kwak et al, 1995). These effects are mediated by phosphorylation of Ser368 by PKC (Lampe et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Connexin 35/36 is phosphorylated at regulatory sites in the retina

Kothmann

Li²,

Burr

et al. 2007

Vis Neurosci

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Connexin 35/36 is the most widespread neuronal gap junction protein in the retina and central nervous system. Electrical and/or tracer coupling in a number of neuronal circuits that express this connexin are regulated by light adaptation. In many cases the regulation of coupling depends on signaling pathways that activate protein kinases such as PKA, and Cx35 has been shown to be regulated by PKA phosphorylation in cell culture systems. To examine whether phosphorylation might regulate Cx35/36 in the retina we developed phospho-specific polyclonal antibodies against the two regulatory phosphorylation sites of Cx35 and examined the phosphorylation state of this connexin in the retina. Western blot analysis with hybrid bass retinal membrane preparations showed Cx35 to be phosphorylated at both the Ser110 and Ser276 sites, and this labeling was eliminated by alkaline phosphatase digestion. The homologous sites of mouse and rabbit Cx36 were also phosphorylated in retinal membrane preparations. Quantitative confocal immunofluorescence analysis showed gap junctions identified with a monoclonal anti-Cx35 antibody to have variable levels of phosphorylation at both the Ser110 and Ser276 sites. Unusual gap junctions that could be identified by their large size (up to 32 μm 2 ) and location in the IPL showed a prominent shift in phosphorylation state from heavily phosphorylated in nighttime, dark-adapted retina to weakly phosphorylated in daytime, light-adapted retina. Both Ser110 and Ser276 sites showed significant changes in this manner. Under both lighting conditions other gap junctions varied from non-phosphorylated to heavily phosphorylated. We predict that changes in the phosphorylation states of these sites correlate with changes in the degree of coupling through Cx35/36 gap junctions. This leads to the conclusion that connexin phosphorylation mediates changes in coupling in some retinal networks. However, these changes are not global and likely occur in a cell type-specific or possibly a gap junction-specific manner.

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Section: Discussionmentioning

confidence: 99%

Connexin 35/36 is phosphorylated at regulatory sites in the retina

Kothmann

Li²,

Burr

et al. 2007

Vis Neurosci

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“…The single channel conductance is about 200 pS, 80 pS and 20 pS, for Cx40, Cx43 and Cx45 channel, respectively [42,62,63]. The conductance values can be influenced by many factors such as intracellular calcium, magnesium, sodium ion concentration, pH, hypoxia and the phosphorylation state of connexins [34,36].…”

Section: The Distribution Of Gap Junctionsmentioning

confidence: 99%

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Magyar

Bányász

Szentandrássy

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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“…Various phospho-forms of Cx43 can be resolved by immunoblotting, making it a useful technique to evaluate its state of phosphorylation (13)(14)(15)20,25,29,30,33,35,37,41,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). Nonetheless, not all changes in the state of phosphorylation of Cx43 alter the electrophoretic mobility of the protein (42).…”

Section: Phosphorylation Of Cxs and Possible Functional Rolesmentioning

confidence: 99%

“…gag-fps and ras oncogen) alter intercellular gap junctional communication and effect of some these agents depends on cell and Cx type (13,16,20,30,(34)(35)(36)38,(41)(42)(43)(44)(45)(46)(47). It has also been suggested that phosphorylation of Cx43 in seryl residues might be involved in a number of different processes including its insertion into the plasma membrane (56), increase in its degradation, changes in unitary conductance of single gap junction channels and closure of gap junction channels (13,16,45,57,61,62).…”

Section: Phosphorylation Of Cxs and Possible Functional Rolesmentioning

confidence: 99%

“…Frequently, a single cell can express more than one Cx, which can be localized in the same (6,7) or in different gap junction plaques (8). Moreover, functional gap junctions can be established in an exogenous expression system (4,5,(9)(10)(11)(12)(13)(14)(15)(16)(17) where the role of protein phosphorylation in channels formed by a particular Cx can be analyzed at the functional level.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of gap junctions by protein phosphorylation

Sáez

Martı́nez

Brañes

et al. 1998

Braz J Med Biol Res

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Gap junctions are constituted by intercellular channels and provide a pathway for transfer of ions and small molecules between adjacent cells of most tissues. The degree of intercellular coupling mediated by gap junctions depends on the number of gap junction channels and their activity may be a function of the state of phosphorylation of connexins, the structural subunit of gap junction channels. Protein phosphorylation has been proposed to control intercellular gap junctional communication at several steps from gene expression to protein degradation, including translational and post-translational modification of connexins (i.e., phosphorylation of the assembled channel acting as a gating mechanism) and assembly into and removal from the plasma membrane. Several connexins contain sites for phosphorylation for more than one protein kinase. These consensus sites vary between connexins and have been preferentially identified in the C-terminus. Changes in intercellular communication mediated by protein phosphorylation are believed to control various physiological tissue and cell functions as well as to be altered under pathological conditions.Correspondence

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Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions.

Cited by 161 publications

References 54 publications

Connexin 35/36 is phosphorylated at regulatory sites in the retina

Connexin 35/36 is phosphorylated at regulatory sites in the retina

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Regulation of gap junctions by protein phosphorylation

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