Connexin Channels, Connexin Mimetic Peptides and ATP Release

Leybaert, Luc; Braet, Katleen; Vandamme, Wouter; Cabooter, Liesbet; Martin, Patricia; Evans, William Howard

doi:10.1080/cac.10.4-6.251.257

Cited by 131 publications

(85 citation statements)

References 25 publications

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“…Hemichannel function has been described also for some connexins under certain experimental conditions (18)(19)(20)(21)(22). In particular, Cx43 has been implicated as an ATP release channel (9,23,24), although calcium wave propagation was found to proceed in Cx43-deficient cells at normal rates (25,26). Similarly, erythrocytes release ATP in the absence of detectable Cx43 expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pannexin 1 in erythrocytes: Function without a gap

Locovei

Dahl

2006

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

463

637

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ATP is a widely used extracellular signaling molecule. The mechanism of ATP release from cells is presently unresolved and may be either vesicular or channel-mediated. Erythrocytes release ATP in response to low oxygen or to shear stress. In the absence of vesicles, the release has to be through channels. Erythrocytes do not form gap junctions. Yet, here we show with immunohistochemical and electrophysiological data that erythrocytes express the gap junction protein pannexin 1. This protein, in addition to forming gap junction channels in paired oocytes, can also form a mechanosensitive and ATP-permeable channel in the nonjunctional plasma membrane. Consistent with a role of pannexin 1 as an ATP release channel, ATP release by erythrocytes was attenuated by the gap junction blocker carbenoxolone. Furthermore, under conditions of ATP release, erythrocytes took up fluorescent tracer molecules permeant to gap junction channels.ATP release ͉ gap junction ͉ hemichannel ͉ dye uptake P annexins represent a recently discovered second family of gap junction proteins in vertebrates (1). Pannexins have no sequence homology with the well known connexin family of vertebrate gap junction proteins. Instead, they are related to innexins, which were originally considered to be exclusively invertebrate gap junction proteins. The functional role of pannexins is unknown. The existence of connexin-specific diseases, despite an overlap of connexin and pannexin expression, suggests a functional role of pannexins that is distinct from that of connexins. Pannexin 1, in addition to forming gap junctions in paired oocytes, also forms nonjunctional membrane channels that provide a passageway from the cytoplasm to the extracellular space for molecules in the size range of second messengers (2, 3). It can be hypothesized that the physiological role of pannexin 1 is formation of a nonjunctional membrane channel.Although the role of ATP as an extracellular signaling molecule is well recognized (4), the release mechanism for ATP from cells to the extracellular space has remained enigmatic. Two general release modes have been proposed: (i) vesicular release akin to the exocytotic release of transmitters and (ii) channel-mediated release. Although vesicular ATP release is well documented (5, 6), it cannot account for all of the ATP release phenomena. In particular, ATP is released from erythrocytes, which, under physiological conditions, are vesicle-free (7). Various channels have been implicated in the process, including CFTR (cystic fibrosis transmembrane conductance regulator), connexin 43 (Cx43) hemichannels, a volumeregulated channel (VRAC), and the purinergic receptor P2X7 (5,6,(8)(9)(10)(11). However, the evidence for their involvement falls short because of questionable specificity of the pharmacological blockers used to determine channel identity.Mechanical stress is a prime stimulus for ATP release in many cell types, including erythrocytes (12). An efficient release mechanism thus may involve a channel that is both mechanosensitive and...

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Section: Discussionmentioning

confidence: 99%

Pannexin 1 in erythrocytes: Function without a gap

Locovei

Dahl

2006

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

463

637

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“…These interfere with GJ formation and inhibit hemichannel activity (Evans and Boitano, 2001; Leybaert et al, 2003). Because their initial characterization (Dahl, Nonner, & Werner, 1994), a series of “Gap” peptides with specificity for certain CX were developed (Abudara et al, 2014; Chaytor, Evans, & Griffith, 1997; Evans and Boitano 2001; Gomes, Srinivas, Van Driessche, Vereecke, & Himpens, 2005; Leybaert et al, 2003). A promising new report shows that Gap19, a nonapeptide derived from the cytoplasmic loop of CX43, inhibits astroglial CX43 hemichannels, while not affecting GJ channels (Abudara et al, 2014).…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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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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Connexin Channels, Connexin Mimetic Peptides and ATP Release

Cited by 131 publications

References 25 publications

Pannexin 1 in erythrocytes: Function without a gap

Pannexin 1 in erythrocytes: Function without a gap

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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

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