Abstract
The classical view of synapses as the functional contact between presynaptic and postsynaptic neurons has been challenged in recent years by the emerging regulatory role of glial cells. Astrocytes, traditionally considered merely supportive elements are now recognized as active modulators of synaptic transmission and plasticity at the now so-called “tripartite synapse.” In addition, an increasing body of evidence indicates that beyond immune functions microglia also participate in various processes aimed to shape synaptic plasticity. Release of neuroactive compounds of glial origin, -process known as gliotransmission-, constitute a widespread mechanism through which glial cells can either potentiate or reduce the synaptic strength. The prevailing vision states that gliotransmission depends on an intracellular Ca2+/exocytotic-mediated release; notwithstanding, growing evidence is pointing at hemichannels (connexons) and pannexin channels (pannexons) as alternative non-vesicular routes for gliotransmitters efflux. In concurrence with this novel concept, both hemichannels and pannexons are known to mediate the transfer of ions and signaling molecules -such as ATP and glutamate- between the cytoplasm and the extracellular milieu. Importantly, recent reports show that glial hemichannels and pannexons are capable to perceive synaptic activity and to respond to it through changes in their functional state. In this article, we will review the current information supporting the “double edge sword” role of hemichannels and pannexons in the function of central and peripheral synapses. At one end, available data support the idea that these channels are chief components of a feedback control mechanism through which gliotransmitters adjust the synaptic gain in either resting or stimulated conditions. At the other end, we will discuss how the excitotoxic release of gliotransmitters and [Ca2+]i overload linked to the opening of hemichannels/pannexons might impact cell function and survival in the nervous system.
Highlights
The traditional view of neurons as the only functional units of synaptic transmission has been challenged in recent decades by the emerging influence of glial cells
Synaptic-mediated changes in the number of functional hemichannels and pannexons at the glial cell membrane could operate in timescales ranging from seconds to hours and through a wide variety of mechanisms
Of particular interest for future studies are regulations related to gating properties, changes in trafficking of preformed channels or in the synthesis rate of de novo channels
Summary
The traditional view of neurons as the only functional units of synaptic transmission has been challenged in recent decades by the emerging influence of glial cells. The mimetic peptide 10Panx, which interacts with an extracellular loop domain of Panx, has been shown to prevent both current and molecular exchange mediated by Panx channels (Pelegrin and Surprenant, 2006; Thompson et al, 2006; Wang et al, 2007) In healthy conditions, both hemichannels and pannexons have been implicated in physiological processes, such as visual processing in the retina (Klaassen et al, 2012; Cenedese et al, 2017), memory and learning (Prochnow et al, 2012; Stehberg et al, 2012), among other brain processes (reviewed in Cheung et al, 2014). The mutation Arg217His of Panx, induces intellectual disability, sensorineural hearing loss, kyphoscoliosis and primary ovarian failure (Shao et al, 2016)
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