Connexins and pannexins: At the junction of neuro-glial homeostasis & disease

Abstract

In the central nervous system (CNS), connexin (Cx)s and pannexin (Panx)s are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal Cx gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, glial gap junctions help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca²⁺ slow wave propagation. Panxs do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission, alongside Cx hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in excessive neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how the disruption of gap junctions and hemichannels lead to abnormal glutamatergic transmission, purinergic signaling, and seizures.

Keywords: astrocyte; connexin; electrical synapse; epilepsy; gap junction; gliotransmission; hemichannel; neuronal excitability; pan-glial network; pannexin; purinergic signaling; seizure; synaptic plasticity.

Figure 1. Connexin and pannexin structure and organization

A Connexin and pannexin hemichannels are hexamers composed of six isoform subunits. Connexin hemichannels may be paired with homotypic or heterotypic hemichannels on adjacent cells to allow exchange of cytoplasmic contents up to 1.5 kDa as gap junctions. Pannexin hemichannels are not thought to form gap junctions due to N-linked glycosylation patterns. B, C Connexins and pannexins are structurally and functionally homologous, but have distinct amino acid sequences. Each subunit possesses four transmembrane domains linked by one intracellular and two extracellular loops. The carboxyl and amine terminals extend into the cytoplasm. The carboxyl tail is the site of regulatory modification and phosphorylation. C Pannexin monomers are structurally related to connexins but glycosylation of the extracellular loop closest to the carboxyl terminal prohibits pannexin hemichannel assembly into functional gap junctions.

Figure 2. The pan-glial network participates in regulating excitatory neuronal transmission through gap junction and hemichannel-mediated functions

Connexin gap junctions control glutamatergic activity indirectly through generation of inward K⁺ currents & spatial K⁺ buffering, activity-dependent astrocyte Ca²⁺ slow wave propagation, and regulation of synaptic invasion by GLT-1 enriched astrocyte process. Model depicts coupling partners for homotypic and heterotypic glial GJs and their cellular expression. Cx43 and Panx1 HCs contribute to synaptic plasticity, inhibitory feedback, and glutamatergic tone by autocrine and paracrine release of synaptic gliotransmitters, including glutamate and ATP.