Photoliberating inositol-1,4,5-trisphosphate triggers ATP release that is blocked by the connexin mimetic peptide gap 26

Braet, Katleen

doi:10.1016/s0143-4160(02)00180-x

Cited by 147 publications

(156 citation statements)

References 67 publications

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“…A diverse range of chemical compounds and connexin mimetic peptides inhibit gap junction intercellular communication, but also act on hemichannels (25,(51)(52)(53). Connexin extracellular loop domain mimetic peptides, GAP26 and GAP27, were developed and shown to block hemichannels when treated for a short period of time (10 -30 min), while longer treatment (more than 1 h) inhibits gap junctions as well (54,55).…”

Section: Discussionmentioning

confidence: 99%

Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading

Siller-Jackson

Burra

et al. 2008

Journal of Biological Chemistry

158

179

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Bone tissues respond to mechanical loading/unloading regimens to accommodate (re)modeling requirements; however, the underlying molecular mechanism responsible for these responses is largely unknown. Previously, we reported that connexin (Cx) 43 hemichannels in mechanosensing osteocytes mediate the release of prostaglandin, PGE 2 , a crucial factor for bone formation in response to anabolic loading. We show here that the opening of hemichannels and release of PGE 2 by shear stress were significantly inhibited by a potent antibody we developed that specifically blocks Cx43-hemichannels, but not gap junctions or other channels. The opening of hemichannels and release of PGE 2 are magnitude-dependent on the level of shear stress. Insertion of a rest period between stress enhances this response. Hemichannels gradually close after 24 h of continuous shear stress corresponding with reduced Cx43 expression on the cell surface, thereby reducing any potential negative effects of channels staying open for extended periods. These data suggest that Cx43-hemichannel activity associated with PGE 2 release is adaptively regulated by mechanical loading to provide an effective means of regulating levels of extracellular signaling molecules responsible for initiation of bone (re)modeling.The skeleton regulates its architecture and mass to meet structural and metabolic needs. To fulfill its structural functions, this complex tissue must adapt to loading and unloading while simultaneously regulating the metabolic demands of the skeleton. Numerous in vivo animal studies show the essential role of mechanical loading for bone formation and remodeling; however, the underlying molecular mechanisms, in particular how bone cells adapt to mechanical stimulation, remain largely uncharacterized.When mechanical forces are applied to bone, several potential stimuli occur including changes in hydrostatic pressure, direct cell strain, fluid flow, and electric potentials. These changes lead to fluid movement through the bone (1-3). Shear stress induced by mechanical loading facilitates the exchange of nutrients and bone modulators, and elicits biochemical responses. Osteocytes are well positioned in the bone to sense the magnitude of mechanical strain and are essential for the skeleton adaptive response to load. Experimental studies have shown that osteocytes are sensitive to stress applied to both intact bone tissue and in cell culture (4 -6). Encased within mineralized tissue, their dendritic morphology allows them to connect through small tunnels called canaliculi to form a threedimensional network not only with adjacent osteocytes but also to connect to cells on the bone surface and bone marrow.Connexins (Cx), 2 gap junction-forming proteins, belong to a multigene family expressing four transmembrane domains. The regions corresponding to transmembrane and extracellular domains are highly conserved. Cx43 has been identified in most types of bone cells (7-13) and is the major connexin expressed in osteocyte-like MLO-Y4 cells and primary osteocy...

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Section: Discussionmentioning

confidence: 99%

Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading

Siller-Jackson

Burra

et al. 2008

Journal of Biological Chemistry

158

179

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“…This model makes several other predictions that will be tested in the context of left-right patterning in the future, because the amount and distribution of serotonin, gap junctions, and ion transporters can be experimentally varied in this system. However, the analysis presented here can be used to model many other signaling systems in addition to serotonin; for example, other small molecules such as cAMP, ATP, and so on are known to pass through gap junctions (Cotrina et al, 1998(Cotrina et al, , 2000Braet et al, 2003;Bao et al, 2004) and have been suggested as candidate morphogens participating in the establishment of positional information (Schiffmann, 1989(Schiffmann, , 1991.…”

Section: Discussionmentioning

confidence: 99%

Mathematical model of morphogen electrophoresis through gap junctions

Esser

Smith

Weaver

et al. 2006

Developmental Dynamics

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Gap junctional communication is important for embryonic morphogenesis. However, the factors regulating the spatial properties of small molecule signal flows through gap junctions remain poorly understood. Recent data on gap junctions, ion transporters, and serotonin during left-right patterning suggest a specific model: the net unidirectional transfer of small molecules through long-range gap junctional paths driven by an electrophoretic mechanism. However, this concept has only been discussed qualitatively, and it is not known whether such a mechanism can actually establish a gradient within physiological constraints. We review the existing functional data and develop a mathematical model of the flow of serotonin through the early Xenopus embryo under an electrophoretic force generated by ion pumps. Through computer simulation of this process using realistic parameters, we explored quantitatively the dynamics of morphogen movement through gap junctions, confirming the plausibility of the proposed electrophoretic mechanism, which generates a considerable gradient in the available time frame. The model made several testable predictions and revealed properties of robustness, cellular gradients of serotonin, and the dependence of the gradient on several developmental constants. This work quantitatively supports the plausibility of electrophoretic control of morphogen movement through gap junctions during early left-right patterning. This conceptual framework for modeling gap junctional signaling-an epigenetic patterning mechanism of wide relevance in biological regulation-suggests numerous experimental approaches in other patterning systems.

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“…Partial uncoupling of gap junctions prior to ischaemia by ischemic-preconditioning preserves the electrical coupling of cells during a subsequent ischemic insult, indicating that a partial closure of gap junctions may play a trigger role in the protection [94,96,154,155]. GAP26 and GAP27 blocks calcium-triggered ATP release mediated by Cx43 hemichannels [156][157][158][159]. Hemichannels are not engaged to gap junctions, and they are open under several physiological and pathophysiological conditions [160].…”

Section: The Possible Antiarrhythmic Effects Of Gap Junction Modulatorsmentioning

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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Photoliberating inositol-1,4,5-trisphosphate triggers ATP release that is blocked by the connexin mimetic peptide gap 26

Cited by 147 publications

References 67 publications

Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading

Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading

Mathematical model of morphogen electrophoresis through gap junctions

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

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