Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

Abstract

The central nervous system (CNS) is composed of a highly heterogeneous population of cells. Dynamic interactions between different compartments (neuronal, glial, and vascular systems) drive CNS function and allow to integrate and process information as well as to respond accordingly. Communication within this functional unit, coined the neuro-glio-vascular unit (NGVU), typically relies on two main mechanisms: direct cell-cell coupling via gap junction channels (GJCs) and paracrine communication via the extracellular compartment, two routes to which channels composed of transmembrane connexin (Cx) or pannexin (Panx) proteins can contribute. Multiple isoforms of both protein families are present in the CNS and each CNS cell type is characterized by a unique Cx/Panx portfolio. Over the last two decades, research has uncovered a multilevel platform via which Cxs and Panxs can influence different cellular functions within a tissue: (1) Cx GJCs enable a direct cell-cell communication of small molecules, (2) Cx hemichannels and Panx channels can contribute to autocrine/paracrine signaling pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as cell-cell adhesion, interactions with the cytoskeleton, and the activation of intracellular signaling pathways. In this paper, we discuss current knowledge on their multifaceted contribution to brain development and to specific processes in the NGVU, including synaptic transmission and plasticity, glial signaling, vasomotor control, and blood-brain barrier integrity in the mature CNS. By highlighting both physiological and pathological conditions, it becomes evident that Cxs and Panxs can play a dual role in the CNS and that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology.

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

“…Interestingly, elevated Ca 2+ signal in astrocytes can in turn triggers a cascade of [Ca 2+ ] i ‐dependent pathways including gliotransmitter release. Indeed, ATP and glutamate release associated to HC activity was demonstrated in glial cells reviewed in (Decrock et al, ): for instance in cultured cells, both Panx1 and Cx43 HCs participate to ATP release in microglial cells (Ma et al, ; Orellana, Montero, & von Bernhardi, ) and in astrocytes (Iglesias, Dahl, Qiu, Spray, & Scemes, ; Kang et al, ); also glutamate release associated to Cx HCs involving Cx43 and Cx32 was demonstrated in astrocytes (Ye et al, ) and in microglial cells (Takeuchi et al, ), respectively. Moreover, in acute or chronic pathological situations, sustained activation of HCs can contribute to an excessive release of ATP and/or glutamate with neurotoxic effects that are alleviated by reducing Cx43 expression or function (Bennett et al, ; Schulz et al, ; Takeuchi & Suzumura, ).…”

Connexin channel and its role in diabetic retinopathy

“…In addition, the possible involvement of pannexin channels also cannot be ignored (Panchin et al, 2000). Multiple studies suggest that these two types of hemichannels have a close relationship and work coordinately in the CNS that differentially regulates the ionic and metabolic fluxes and cellular function (Decrock et al, 2015; Jiang and Penuela, 2016). …”

Regulation of Connexins Expression Levels by MicroRNAs, an Update

“…Cx26 is detected at early stages of the development, while Cx32 and Cx43 are expressed throughout entire brain development and adulthood (Nadarajah et al, 1997). After birth, Cxs play important roles in brain functions, coordinating the activity between neurons and also between glial cells (Pereda, 2014; PosÅuszny, 2014; Decrock et al, 2015; Del Rio et al, 2015). Changes in expression levels and/or channel function formed by several different Cxs have been associated with a number of central nervous system (CNS) disorders.…”