Molecular pathways of pannexin1-mediated neurotoxicity

Molecular pathways of pannexin1-mediated neurotoxicity

Blog Article

Pannexin1 (Panx1) forms nonselective membrane channels, structurally similar to gap junction pentair hose hemichannels, that is permeable to ions, nucleotides and other small molecules below 900 Da.Panx1 activity is implicated in paracrine signaling and inflammasome regulation.Recent studies in different animal models showed that Panx1 overactivation correlates with a selective demise of several types of neurons, including retinal ganglion cells, brain pyramidal and enteric neurons.

The list of Panx1 activators includes extracellular ATP, glutamate, high K+, Zn2+, fibroblast growth factors (FGFs), pro-inflammatory cytokines and elevation of intracellular Ca2+.Most of these molecules are released following mechanical, ischemic or inflammatory injury of the CNS, and rapidly activate this channel.As a result, prolonged opening of Panx1 channel induced by these danger signals trigger a cascade of neurotoxic events capable of killing cells.

The most vulnerable cell type are neurons that express high levels of Panx1.Experimental evidence suggests that Panx1 channels mediate at least two distinct neurotoxic processes: increased permeability of the plasma membrane and activation of the inflammasome in neurons and glia.Importantly, either pharmacological or genetic inactivation of Panx1 suppresses both these processes, providing a marked protection in several disease and injury models.

These findings indicate that external danger signals generated after diverse types of injuries converge to activate Panx1.In this review we discuss molecular mechanisms associated with Panx1 toxicity and the arcade smokey the bear belt crosstalk between different pathways.