Connexins and Pannexins: New Insights into Microglial Functions and Dysfunctions

Abstract

Under physiological conditions, microglia adopt a resting phenotype associated with the production of anti-inflammatory and neurotrophic factors. In response to a wide variety of insults, these cells shift to an activated phenotype that is necessary for the proper restoration of brain homeostasis. However, when the intensity of a threat is relatively high, microglial activation worsens the progression of damage rather than providing protection, with potentially significant consequences for neuronal survival. Coordinated interactions among microglia and other brain cells, including astrocytes and neurons, are critical for the development of timely and optimal inflammatory responses in the brain parenchyma. Tissue synchronization is in part mediated by connexins and pannexins, which are protein families that form different plasma membrane channels to communicate with neighboring cells. Gap junction channels (which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells to coordinate electrical and metabolic coupling. Hemichannels (HCs) and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra- and extracellular compartments and serve as diffusion pathways for the exchange of ions and small molecules. In this review article, we discuss the available evidence concerning the functional expression and regulation of connexin- and pannexin-based channels in microglia and their contributions to microglial function and dysfunction. Specifically, we focus on the possible implications of these channels in microglia-to-microglia, microglia-to-astrocyte and neuron-to-microglia interactions in the inflamed brain.

Connexin-Based Channels and RhoA/ROCK Pathway in Angiotensin II-Induced Kidney Damage

“…HCs are fundamental pathways for the exchange of ions and small molecules between the intra-and extracellular compartments. These structures can be opened under physiological and pathophysiological conditions, allowing the release of paracrine and autocrine signaling molecules to the extracellular medium (e.g., adenosine triphosphate [ATP], glutamate, NAD + , and prostaglandin E2 [PGE2]) [35]. Each type of channel formed by the Cxs has unique gate properties, in addition to a characteristic conductance and permeability features [36][37][38].…”

Connexins in health and disease

“…Cx43 levels and dye coupling are reduced in astrocytes when co‐cultured with microglia. Further investigation showed interleukin‐1β and tumor necrosis factor‐α from activated microglia are the main soluble factors affecting Cx43 expression on astroglia . Watanabe et al.…”

“…Connexin expression among microglia depends heavily on the context of their activation. In the resting state, Cx32 and Cx36 are expressed, and when they are activated the expression levels of Cx29, Cx32, Cx36 and Cx43 are elevated . Neighboring microglial cells communicate with each other through Cx43 gap junctions, and other connexins and pannexin (Panx1) form hemichannels for the release of ATP and other cytokines, calcium ions, glutamate, and so on.…”

“…P2XRs) on microglia. Activated microglia release glutamate thorough Cx43/Cx32 or Panx1 hemichannels, which leads to neuronal damage …”

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

“…An important aspect is the modulatory action that microglia exert on astroglial hemichannel/pannexon activity, which seems to be decisive for neuronal function and survival (Montero and Orellana, 2015; Gajardo-Gómez et al, 2016; Orellana et al, 2016). In fact, microglia subjected to inflammatory conditions release TNF-α and IL-1β, resulting in the further increase of Cx43 hemichannel currents in astrocytes in cell cultures and hippocampal slices (Retamal et al, 2007; Abudara et al, 2015).…”