Connexin and pannexin mediated cell-cell Communications

The Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, NY, 10461, USA.
Neuron Glia Biology (Impact Factor: 6.64). 08/2007; 3(3):199-208. DOI: 10.1017/S1740925X08000069
Source: PubMed


In this review, we briefly summarize what is known about the properties of the three families of gap junction proteins, connexins, innexins and pannexins, emphasizing their importance as intercellular channels that provide ionic and metabolic coupling and as non-junctional channels that can function as a paracrine signaling pathway. We discuss that two distinct groups of proteins form gap junctions in deuterostomes (connexins) and protostomes (innexins), and that channels formed of the deuterostome homologues of innexins (pannexins) differ from connexin channels in terms of important structural features and activation properties. These differences indicate that the two families of gap junction proteins serve distinct, complementary functions in deuterostomes. In several tissues, including the CNS, both connexins and pannexins are involved in intercellular communication, but have different roles. Connexins mainly contribute by forming the intercellular gap junction channels, which provide for junctional coupling and define the communication compartments in the CNS. We also provide new data supporting the concept that pannexins form the non-junctional channels that play paracrine roles by releasing ATP and, thus, modulating the range of the intercellular Ca(2+)-wave transmission between astrocytes in culture.

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Available from: Eliana Scemes
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    • "In the presence of apyrase (50 U/ml) the transmission of Ca2+ signals was confined to cells in the immediate neighborhood of the mechanically-stimulated cells (Figure 7C). We have shown that activation of Panx1 and P2X7R in astrocyte cultures contributes to ICW transmission and modulates the range of ICW spread by providing a feed-forward mechanism of ATP-induced ATP release [37], [38], [45], [63]. To specifically investigate the involvement of Panx1 and P2X7R in ICW transmission we exposed the cells to LDPBS and MFQ. "
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    ABSTRACT: Urothelial cells respond to bladder distension with ATP release, and ATP signaling within the bladder and from the bladder to the CNS is essential for proper bladder function. In other cell types, pannexin 1 (Panx1) channels provide a pathway for mechanically-induced ATP efflux and for ATP-induced ATP release through interaction with P2X7 receptors (P2X7Rs). We report that Panx1 and P2X7R are functionally expressed in the bladder mucosa and in immortalized human urothelial cells (TRT-HU1), and participate in urothelial ATP release and signaling. ATP release from isolated rat bladders induced by distention was reduced by the Panx1 channel blocker mefloquine (MFQ) and was blunted in mice lacking Panx1 or P2X7R expression. Hypoosmotic shock induced YoPro dye uptake was inhibited by MFQ and the P2X7R blocker A438079 in TRT-HU1 cells, and was also blunted in primary urothelial cells derived from mice lacking Panx1 or P2X7R expression. Rinsing-induced mechanical stimulation of TRT-HU1 cells triggered ATP release, which was reduced by MFQ and potentiated in low divalent cation solution (LDPBS), a condition known to enhance P2X7R activation. ATP signaling evaluated as intercellular Ca2+ wave radius was significantly larger in LDPBS, reduced by MFQ and by apyrase (ATP scavenger). These findings indicate that Panx1 participates in urothelial mechanotransduction and signaling by providing a direct pathway for mechanically-induced ATP release and by functionally interacting with P2X7Rs.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "stem cells which implement regeneration are not locally controlled ( since the cells were direct neighbours until the scalpel separated them ) but must communicate with the remaining tissue to decide what anatomical structures must be formed . It was shown recently that this long - range communication occurs via GJ - mediated electrical synapses ( Scemes et al . 2007 ; Marder , 2009 ; Pereda et al . 2013 ) , and works together with a bioelectric circuit that determines head vs . tail identity in each end ' s blastema ( Beane et al . 2011 , 2013 ) . Importantly , it was shown that inhibition of this gap junction - mediated communication , using octanol , results in worm fragments forming heads at bot"
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    ABSTRACT: Pattern formation, as occurs during embryogenesis or regeneration, is the crucial link between genotype and the functions upon which selection operates. Even cancer and aging can be seen as challenges to the continuous physiological processes that orchestrate individual cell activities toward the anatomical needs of an organism. Thus, the origin and maintenance of complex biological shape is a fundamental question for cell, developmental, and evolutionary biology, as well as for biomedicine. It has long been recognized that slow bioelectrical gradients can control cell behaviors and morphogenesis. Here, I review recent molecular data that implicate endogenous spatio-temporal patterns of resting potentials among non-excitable cells as instructive cues in embryogenesis, regeneration, and cancer. Functional data have implicated gradients of resting potential in processes such as limb regeneration, eye induction, craniofacial patterning, and head-tail polarity, as well as in metastatic transformation and tumorigenesis. The genome is tightly linked to bioelectric signaling, via ion channel proteins that shape the gradients, downstream genes whose transcription is regulated by voltage, and transduction machinery that converts changes in bioelectric state to second-messenger cascades. However, the data clearly indicate that bioelectric signaling is an autonomous layer of control not reducible to a biochemical or genetic account of cell state. The real-time dynamics of bioelectric communication among cells are not fully captured by transcriptomic or proteomic analyses, and the necessary-and-sufficient triggers for specific changes in growth and form can be physiological states, while the underlying gene loci are free to diverge. The next steps in this exciting new field include the development of novel conceptual tools for understanding the anatomical semantics encoded in non-neural bioelectrical networks, and of improved biophysical tools for reading and writing electrical state information into somatic tissues. Cracking the bioelectric code will have transformative implications for developmental biology, regenerative medicine, and synthetic bioengineering.
    Preview · Article · Jun 2014 · The Journal of Physiology
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    • "Some connexin hemichannels, particularly those formed by connexin isoforms 26, 32, 37, and 43 were also shown to pass ATP molecules in response to phosphorylation, intracellular and extracellular calcium change and other stimuli (Zhao et al., 2005; De Vuyst et al., 2006; Scemes et al., 2007; Shestopalov and Panchin, 2008; Silverman et al., 2008; Sonntag et al., 2009; Bao et al., 2012). However, the two families of channel proteins have quite distinct physiological properties, particularly the ability to form full vs. partial channels in vivo and in the spectrum of binding partners (Scemes et al., 2007; Shestopalov and Panchin, 2008; Silverman et al., 2008; Bao et al., 2012). In contrast to connexins, pannexins are insensitive to physiological levels of extracellular calcium, possess faster kinetics of pore opening, larger unitary conductance and very weak voltage gating (Bruzzone et al., 2003; Bao et al., 2004). "
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    ABSTRACT: Tissue injury involves coordinated systemic responses including inflammatory response, targeted cell migration, cell-cell communication, stem cell activation and proliferation, and tissue regeneration. The inflammatory response is an important prerequisite for regeneration. Multiple studies suggest that extensive cell-cell communication during tissue regeneration is coordinated by purinergic signaling via extracellular ATP. Most recent data indicates that ATP release for such communication is mediated by hemichannels formed by connexins and pannexins. The Pannexin family consists of three vertebrate proteins (Panx 1, 2, and 3) that have low sequence homology with other gap junction proteins and were shown to form predominantly non-junctional plasma membrane hemichannels. Pannexin-1 (Panx1) channels function as an integral component of the P2X receptor (P2XR) (purinergic) signaling pathway and is arguably the major contributor to pathophysiological ATP release. Panx1 is expressed in many tissues, with highest levels detected in developing brain, retina and skeletal muscles. Panx1 channel expression and activity is reported to increase significantly following injury/inflammation and during regeneration and differentiation. Recent studies also report that pharmacological blockade of the Panx1 channel or genetic ablation of the Panx1 gene cause significant disruption of progenitor cell migration, proliferation, and tissue regeneration. These findings suggest that pannexins play important roles in activation of both post-injury inflammatory response and the subsequent process of tissue regeneration. Due to wide expression in multiple tissues and involvement in diverse signaling pathways, pannexins and connexins are currently being considered as therapeutic targets for traumatic brain or spinal cord injuries, ischemic stroke and cancer. The precise role of pannexins and connexins in the balance between tissue inflammation and regeneration needs to be further understood.
    Full-text · Article · Feb 2014 · Frontiers in Physiology
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