Glaucoma comprises a group of ocular disorders that exhibit characteristic optic nerve degeneration (glaucomatous optic neuropathy, GON), associated with concomitant visual field loss, and often, increased intraocular pressure (lOP). In many individuals, reduction of lOP ameliorates vision loss, but many others continue to lose vision despite pressure lowering. There are no therapies that directly target and prevent GON. While the exact underlying mechanisms of GON are being elucidated, specific patho-physiological changes (such as mechanical trauma and ischemia) ultimately lead to the death of retinal ganglion cells and their axons. We have directed our attention to a newly discovered family of proteins; acid-sensing ion channels (ASICs), which appear to be significant in brain injury. The ASICs are proton-activated sodium selective cation channels comprised of six subtypes that are expressed throughout the nervous system. They respond to acidic and mechanical stimuli activating in response to acidosis and swelling, notable features of ischemic brain injury. Recent studies reveal that rabbit retinal neurons and gila express ASIC messenger RNA. Thus ASICs could respond to mechanical stimulation in the eye from increased intraocular pressure and/or ischemic changes within the retina and optic nerve, two mechanisms commonly implicated in the pathogenesis of GON. These findings make retinal ASICs attractive cellular mediators for investigation. Our preliminary studies support a role of ASICs in the retina: immunoblot analysis of the ASIC2a subtype reveals a dramatic increase in expression in the retina and optic nerve of glaucomatous human tissue relative to age-matched controls. Upregulation of brain ASIC2a may be important for cell survival as cells expressing ASIC2a are less responsive to injury. Our laboratory has shown that neurons that survive an ischemic insult have increased levels of ASIC2a protein, suggesting a neuroprotective role for ASIC2a. This prediction is supported by the observation that ASIC2a alters the ion channel activation properties when it is complexed with ASICla, a subtype that is implicated in cell injury. Cells expressing homomeric ASICla channels are injured by low pH and modeled ischemia, while heteromeric ASICla/2a channels are less vulnerable to injury. Physiological studies lend insight into this finding; the pH of half-maximal activation (pHo.s) for ASIC2a channels is 4.35, for ASICla channels is 6.2, whereas ASICla/ASIC2a heteromeric channels is 4.8. This could be significant in the context of injury, where intracellular calcium overload has been implicated as a primary mechanism of neuronal injury. The goal of these studies is to characterize fully the expression of ASIC2a in the retina and optic nerve of normal and glaucomatous tissue, and to determine whether ASIC2a enhances cell survival in response to injury and could potentially serve as a therapeutic target for the treatment or prevention of glaucoma.
| Chai, Sunghee; Li, Minghua; Lan, JingQuan et al. (2007) A kinase-anchoring protein 150 and calcineurin are involved in regulation of acid-sensing ion channels ASIC1a and ASIC2a. J Biol Chem 282:22668-77 |
