Dock3-NMDA receptor interaction as a target for glaucoma therapy.
Glaucoma is a neurodegenerative disease of the eye and it is one of the major causes of blindness. Glaucoma is usually associated with elevated intraocular pressure (IOP) and the current therapy focuses on reduction of IOP. However, neuroprotective strategies could also be beneficial for treatment of glaucoma because the pathology of the disease involves retinal ganglion cell (RGC) death and damage to the optic nerve. Dedicator of cytokinesis 3 (Dock3) is an atypical guanine exchange factor (GEF) that belongs to a family of Dock proteins, Dock1-11. Dock3 exerts neuroprotective effects on the retina and optic nerve, and studies revealed that some of the Dock3-mediated effects are GEF-independent. One of these mechanisms is that Dock3 directly binds to the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor. Upon stimulation by NMDA or optic nerve crush, overexpression of Dock3 promotes internalization and degradation of the NMDA receptor in the retina in vivo. It is suggested that this process is mediated by inhibition of Fyn, a Src family tyrosine kinase. Reduction in NMDA receptor expression results in decreased excitotoxic damage and oxidative stress, thereby promoting RGC survival. In this review, we discuss the therapeutic potential of neuroprotection for glaucoma and the effects of Dock3 on NMDA receptors. We also discuss apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein kinase kinase kinase that is a key regulator of cellular responses to oxidative stress, as an innovative therapeutic target for glaucoma.
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Atsuko
A
Kimura
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. namekata-kz@igakuken.or.jp.
Kazuhiko
K
Namekata
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Xiaoli
X
Guo
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Chikako
C
Harada
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Takayuki
T
Harada
D000818:Animals; D005901:Glaucoma / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
C485840:DOCK3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate