title: Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors.
abstract: Mechanical deformation produces complex effects on neuronal systems, some of which can lead to dysfunction and neuronal death. While astrocytes are known to respond to mechanical forces, it is not clear whether neurons can also respond directly. We examined mechanosensitive ATP release and the physiological response to this release in isolated retinal ganglion cells. Purified ganglion cells released ATP upon swelling. Release was blocked by carbenoxolone, probenecid or peptide (10)panx, implicating pannexin channels as conduits. Mechanical stretch of retinal ganglion cells also triggered a pannexin-dependent ATP release. Whole cell patch clamp recording demonstrated that mild swelling induced the activation of an Ohmic cation current with linear kinetics. The current was inhibited by removal of extracellular ATP with apyrase, by inhibition of the P2X(7) receptor with A438079, zinc, or AZ 10606120, and by pannexin blockers carbenoxolone and probenecid. Probenecid also inhibited the regulatory volume decrease observed after swelling isolated neurons. Together, these observations indicate mechanical strain triggers ATP release directly from retinal ganglion cells and that this released ATP autostimulates P2X(7) receptors. Since extracellular ATP levels in the retina increase with elevated intraocular pressure, and stimulation of P2X(7) receptors on retinal ganglion cells can be lethal, this autocrine response may impact ganglion cells in glaucoma. It remains to be determined whether the autocrine stimulation of purinergic receptors is a general response to a mechanical deformation in neurons, or whether preventing ATP release through pannexin channels and blocking activation of the P2X(7) receptor, is neuroprotective for stretched neurons.
authors.affiliation: Department of Anatomy and Cell Biology, University of Pennsylvania, 440 Levy Building, 240 S. 40th St, Philadelphia, PA 19104, USA.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Xia
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lim
authors.forename: Wennan
authors.initials: W
authors.lastname: Lu
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Beckel
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Macarak
authors.forename: Alan M
authors.initials: AM
authors.lastname: Laties
authors.forename: Claire H
authors.initials: CH
authors.lastname: Mitchell
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D017630:Connexins / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; D058486:Receptors, Purinergic P2X7; C479936:pannexin 1, rat; D000255:Adenosine Triphosphate