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C.-J. Dong, Y. Guo, L. Wheeler, W. A. Hare; 2 Adrenergic Modulation of L-Type Ca++ Channel and NMDA Receptor Activity in a Mammalian Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3617.
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© ARVO (1962-2015); The Authors (2016-present)
α2 receptor agonists, such as brimonidine, have been shown to protect retinal ganglion cells (RGCs) in animal models of glaucoma and acute retinal ischemia. However, the mechanism of action as well as the physiological role of the α2 adrenergic system in the retina is not well understood. This work was set out to explore the mechanism of protection and physiological role of α2 adrenergic system in retinal signal processing.
Both Ca++ imaging and electrophysiology (patch clamp) were used to characterize the effect of α2 agonists on high K+- and NMDA-elicited intracellular free Ca++ signals and NMDA-elicited whole-cell currents. These optical and electrophysiological measurements were conducted in rat ex vivo retinal preparations (retinal slice and isolated retina). High K+ and NMDA-containing Ringers were delivered rapidly through a custom-made multi-channel local perfusion system. Retinal ganglion cells (RGCs) were identified by intracellular labeling.
In retinal slices, an 8 sec application of high K+ Ringer elicited at the inner plexiform layer (IPL) a robust Ca++ signal which was abolished by perfusing with 0 Ca++ Ringer and suppressed dramatically by specific L-type Ca++ channel blockers, such as nimodipine and SR 33805. The Ca++ signal was also suppressed in a dose-dependent manner by brimonidine and other α2 agonists, such as medetomidine. The suppressive action of the α2 receptor agonists can be completely blocked by specific α2 receptor antagonists, such as atipamezole, yohimbine, and rauwolscine. In in situ RGCs in isolated retinas, simultaneous whole-cell recording and Ca++ imaging were performed. An 8 sec application of NMDA in 0 Mg++ Ringer elicited a prominent inward current and Ca++ signal in RGCs that were voltage-clamped at -70 mV. The NMDA-induced current and Ca++ signal were completely blocked by a selective NMDA receptor antagonist (D-AP5) and NMDA channel blocker (memantine). These NMDA-induced responses were also significantly attenuated by brimonidine and this suppressive effect of brimonidine was blocked by specific α2 receptor antagonists.
Our results demonstrate for the first time in the mammalian retina and CNS that the activity of L-type Ca++ channels and NMDA receptor channels can be modulated by the α2 adrenergic system. These results suggest that brimonidine may protect RGCs in animal models of glaucoma and acute retinal ischemia by preventing abnormal elevation of intracellular free Ca++ through both voltage- and ligand-gated Ca++ channels.
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