Beneficial and Detrimental Remodeling of Glial Connexin and Pannexin Functions in Rodent Models of Nervous System Diseases

Abstract

A variety of glial cell functions are supported by connexin and pannexin proteins. These functions include the modulation of synaptic gain, the control of excitability through regulation of the ion and neurotransmitter composition of the extracellular milieu and the promotion of neuronal survival. Connexins and pannexins support these functions through diverse molecular mechanisms, including channel and non-channel functions. The former comprise the formation of gap junction-mediated networks supported by connexin intercellular channels and the formation of pore-like membrane structures or hemichannels formed by both connexins and pannexins. Non-channel functions involve adhesion properties and the participation in signaling intracellular cascades. Pathological conditions of the nervous system such as ischemia, neurodegeneration, pathogen infection, trauma and tumors are characterized by distinctive remodeling of connexin expression and function. However, whether these changes can be interpreted as part of the pathogenesis, or as beneficial compensatory effects, remains under debate. Here we review the available evidence addressing this matter with a special emphasis in mouse models with selective manipulation of glial connexin and pannexin proteins in vivo. We postulate that the beneficial vs. detrimental effects of glial connexin remodeling in pathological conditions depend on the impact of remodeling on the different connexin and pannexin channel and non-channel functions, on the characteristics of the inflammatory environment and on the type of interaction among glial cells types.

Channels to consciousness: a possible role of gap junctions in consciousness

“…Pannexin channel trafficking and channel gating is affected by post-translational modifications, such as phosphorylation, N-glycosylation, and S-nitrosylation (Boyce et al 2018). Like connexins, pannexins have been implicated in several pathologies including neurodegenerative diseases, ischemia, spinal cord injury, cancerogenesis, and neuropathic pain (Brocardo et al 2019).…”

“…They have also been implicated in the control of the blood-brain barrier, regulation of extracellular pH, control of extracellular ion concentrations (including potassium and calcium), the uptake, turnover, binding, and release of major excitatory and inhibitory neurotransmitters, growth factors, and signaling molecules (including glutamate, gamma-aminobutyric acid, and adenosine trisphosphate). Owing to these various actions and functions, astrocytes are extremely important for the regulation of neurotransmission, synaptic plasticity, neuronal excitability, and synchronization (Brocardo et al 2019;Perea et al 2009;Xin and Bonci 2018).…”

Chronic Stress and Gonadectomy Affect the Expression of Cx37, Cx40 and Cx43 in the Spinal Cord

“…Gap junction intercellular communications (GJIC) in the CNS are known as electric synapses [14]. They are composed of two opposed hexameric formations of six connexins (Cxs) on each participating cell known as connexon [15,16].…”

“…By interconnecting the cytoplasm of two adjacent cells, the channel function of GJIC provides a robust synchronization of electrical activity between groups of neurons, glia, or between each other [17]. In addition, GJIC also mediates in the exchange of small-molecule metabolites such as ATP and glutamate [14,15,18]. Moreover, nonpaired connexons also known as hemichannels found on nonjunctional regions of the cell membranes, provide leakage of cytosolic molecules in the extracellular medium and vice versa under certain conditions [19,20].…”

“…Moreover, nonpaired connexons also known as hemichannels found on nonjunctional regions of the cell membranes, provide leakage of cytosolic molecules in the extracellular medium and vice versa under certain conditions [19,20]. Non-channel functions of Cxs include intracellular cascade signaling and modulation of cellular adhesion properties [14]. The Cx family of proteins is encoded by 20 genes in rodents and 21 genes in humans, and each protein is named according to its molecular weight [21].…”