Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

Abstract

In a healthy brain, microglia exhibit a resting surveillance state associated with active explo‐ ration of their environment for exogenous or endogenous signals representing a threat to the homeostasis [1-5]. When physiological balance is impaired in the central nervous system (CNS), resting phenotype of microglia shift to a reactive phenotype with different degrees of activation according to the nature of the stimuli and the context. During intense CNS inflam‐ mation, rather than show a repair-orientated activity profile, reactive microglia constitute a source of toxic factors and participate in the recruitment of non-resident brain cells involved in the innate immune response, which worsen brain damage. The brain performs exception‐ ally complex and dynamic tasks that depend on the coordinated interaction of glial cells, therefore it is conceivable that impairment of intercellular signaling and coordination among microglia could play an important role on several CNS disorders. In vertebrate cells, this synchronization is in part mediated by gap junctions [6-10]. They are aggregates of in‐ tercellular channels termed gap junction channels that allow direct, but selective, cytoplas‐ mic continuity between contacting cells, promoting the exchange of ions (allowing eletrical coupling), metabolites (e.g., ADP, glucose, glutamate and glutathione) and second messen‐ gers (e.g., cAMP and IP3)[11-16]. Whereas a gap junction channel is formed by the serial docking of two hemichannels each one contributed by one of two adjacent cells, each hemi‐ channel is composed by six protein subunits termed connexins (Fig. 1). The latter belong to a highly conserved protein family encoded by 21 genes in human and 20 in mouse with ortho‐ logs in other vertebrate species [17-19]. Connexins are abundantly expressed in cells of the CNS, and they are named after their predicted molecular mass expressed in kDa, so that connexin43 (Cx43) has a molecular mass of ~43 kDa.