Role of Connexins and Pannexins in Ischemic Stroke

Abstract

Synaptic plasticity requires careful synchronization and coordination of neurons and glial cells via various mechanisms of intercellular communication. Among them, are those mediated by i) connexin gap junction channels (GJCs), ii) connexin hemichannels and iii) pannexin channels. Whereas GJCs directly communicate the cytoplasm of contacting cells and coordinate electric and metabolic activities, connexin hemichannels and pannexin channels serve as diffusional pathways for ions and small molecules between the intra- and extracellular compartments. A growing body of evidence has revealed that intercellular communication could be critical in the spread of protective and/or deleterious signals during stroke. Here, we review current findings on the regulation of connexin- and pannexin-based channels in ischemic stroke and how they contribute to cell damage observed in pathology. Depending on intensity of the ischemic event, brain region and connexin subtype expressed, GJCs may provide proper diffusion of energy metabolites and dissipation of toxic substances, whereas, in other circumstances, they could increase damage by spreading toxic molecules. Alternatively, connexin hemichannel and pannexin channel opening may favor the release of neurotoxic substances (e.g., glutamate), but in other cases, they may confer neuroprotection against an ischemic episode by the phenomenon of ischemic preconditioning. Development of new drug modulators using in silico devices for connexin and pannexin-based channels will be crucial for future therapies against stroke.

Connexin Hemichannels in Astrocytes: An Assessment of Controversies Regarding Their Functional Characteristics

“…Knock-out models include an astrocytic-specific Cx43 knock-out, a Cx30 knock-out, a double knock-out targeting both astrocytic connexins, as well as a knock-in model of Cx43G138R [10, [75][76][77]. Together with pharmacological experiments, these mouse models have yielded insights about the diverse roles of these connexin hemichannels, both in normal and pathological situations (e.g., vasoconstriction, synaptic transmission, modulation of excitability of sensory neurons, Alzheimer's disease, neuropathic pain, cell damage in brain trauma, ischemic stroke, HIVmediated brain dysfunction, and brain alterations following prenatal nicotine exposure, [17, 21, [78][79][80][81][82][83][84][85]). The downside of the gene alteration strategy is the frequent discovery of inadvertent effects on other factors in these mice: The widespread transcriptome alterations observed in mice with knock-out or knock-down of Cx43 [86,87] can, in some cases, lead to changes in membrane transport mechanisms unrelated to Cx43, but which may then be mistakenly construed to be Cx43 effects.…”

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

“…In the normal brain, hemichannels and pannexons mediate the physiological release of gliotransmitters (e.g., ATP, glutamate, D -serine, lactate), serving as crucial players during ischemic tolerance, fear memory consolidation, synaptic transmission, neuronal oscillations and glucose sensing (Cheung et al, 2014). Nevertheless, the uncontrolled opening of these channels seem to be critical to the initiation and maintenance of the homeostatic imbalances that are observed in diverse CNS diseases (Salameh et al, 2013; Orellana et al, 2014a, 2016). …”

Fluorescent dyes as a reliable tool in P2X7 receptor-associated pore studies

“…The most studied mammalian high conductance channels found are the connexin hemichannels (Cx43, Cx32 and other), pannexin-1, maxi-anion channel, plasma membrane voltage dependent anionic channel (plasma VDAC), maxi-K channel, maitotoxininduced pore, transient receptor potential vanilloid type-1 (TRPV1), transient receptor potential ankhirin type-1 (TRPA1) and ATP-activated P2X pores (P2X2, P2X4 and P2X7 receptors). Though they have distinct ionic selectivity, they all allow passage of both mono and divalent ions and molecules of up to 1,000 Da and permit the entry of the anionic ATP 4 − molecule (Pellegatti et al 2005;Nagasawa et al 2009;Sadananda et al 2009;Yip et al 2009;Lohman et al 2012) and glutamate (Liu et al 2006, León et al 2008, Musella et al 2009Sun et al 2009;Orellana et al 2014). The biophysical properties and some physiological aspects of these channels permeable to large solutes are well discussed in the published reviews (Alves et al 2014;Ferreira et al 2012;Contreras 2012).…”