Connexin43- and Pannexin-Based Channels in Neuroinflammation and Cerebral Neuropathies

Abstract

Connexins (Cx) are largely represented in the central nervous system (CNS) with 11 Cx isoforms forming intercellular channels. Moreover, in the CNS, Cx43 can form hemichannels (HCs) at non-junctional membrane as does the related channel-forming Pannexin1 (Panx1) and Panx2. Opening of Panx1 channels and Cx43 HCs appears to be involved in inflammation and has been documented in various CNS pathologies. Over recent years, evidence has accumulated supporting a link between inflammation and cerebral neuropathies (migraine, Alzheimer’s disease (AD), Parkinson’s disease (PD), major depressive disorder, autism spectrum disorder (ASD), epilepsy, schizophrenia, bipolar disorder). Involvement of Panx channels and Cx43 HCs has been also proposed in pathophysiology of neurological diseases and psychiatric disorders. Other studies showed that following inflammatory injury of the CNS, Panx1 activators are released and prolonged opening of Panx1 channels triggers neuronal death. In neuropsychiatric diseases, comorbidities are frequently present and can aggravate the symptoms and make therapeutic management more complex. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving inflammatory pathways and Panx1 channels or Cx43 HCs. Thus, anti-inflammatory therapy opens perspectives of targets for new treatments and could have real potential in controlling a cerebral neuropathy and some of its comorbidities. The purpose of this mini review is to provide information of our knowledge on the link between Cx43- and Panx-based channels, inflammation and cerebral neuropathies.

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…A further argument for the involvement of P2X7Rs in the etiology of MD is supplied by studies which show that inhibition or genetic abrasion of the P2X7R-Panx-1 pore complex suppresses spreading depolarization and neuroinflammation in mice (Chen et al, 2017). This is in perfect agreement with findings that Cx43-and Panx-1-based channels participate in the induction of neuroinflammation and cerebral neuropathies (Sarrouilhe et al, 2017; for further considerations on the role of connexins/pannexins in MD, see the section ''Inhibited Astrocytic ATP Release in the Pre-frontal Cortex'').…”

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

“…A potential mechanism leading to an increase in DAMP secretion, which initiates sterile brain inflammation by activating the ComC in a mannan-binding lectin (MBL)-dependent manner, involves the aberrant function of pannexins ( 21 ). These proteins are distant homologs of connexins; while unable to form gap junctions they form transmembrane channels on the cell surface, releasing molecules such as ATP from activated cells ( 20 ).…”

Oligodendrocytes Remodel the Genomic Fabrics of Functional Pathways in Astrocytes

“…Figure 8illustrates this finding by the changes in the coordinated expression of Gja1 and Panx1 (encoding the intercellular major gap junction channel forming protein Cx43), and the ATP release channel protein Panx1) with actin-cytoskeleton (8a) and circadian rhythm (8b) genes. Both Cx43 and Panx1 are well-documented for their important roles in the physio-pathology of the Central Nervous System[52,53]. This analysis shows that the expression synergism of Panx1 with Fgf18, Itga2b and Pdgfd in isolated (control) astrocytes was reversed to an antagonistic coordination by the proximity of Oli-neu cells (in insert), while the antagonism of Gja1 with Pip4k2b was turned into synergism.…”