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2 Adrenergic Receptor–Mediated Modulation of Cytosolic Ca⁺⁺ Signals at the Inner Plexiform Layer of the Rat Retina

From the Department of Biological Sciences, Allergan Pharmaceuticals, Inc., Irvine, California.

PURPOSE. Compelling evidence suggests that 2 agonists, such as brimonidine, protect retinal ganglion cells (RGCs) from injury in a wide range of animal models. However, the mechanism of action for this protection and the physiological role of the 2 adrenergic system in the retina is not well understood. A major goal of this work was to explore the role of the 2 adrenergic system in the modulation of cytosolic Ca²⁺ signaling at retinal synaptic layers, particularly the inner plexiform layer (IPL), where communication between RGCs and their presynaptic cells takes place.

METHODS. Functional Ca²⁺ imaging at the inner plexiform layer (IPL) and outer plexiform layer (OPL) of living rat retinal slices was conducted with a high-speed confocal system. The relative changes of cytosolic free Ca²⁺ were monitored with the fluorescent Ca²⁺ dye fluo-4. The Ca²⁺ signal was elicited by membrane depolarization produced by a high K⁺ (40 mM) Ringer solution that was delivered rapidly and briefly to the test regions of the retinal slice by a custom-made multichannel local perfusion system.

RESULTS. A brief application (8 seconds) of high K⁺ Ringer elicited a robust cytosolic Ca²⁺ increase at the IPL and OPL. In both cases, this Ca²⁺ signal was eliminated by nimodipine, a selective L-type voltage-gated Ca²⁺-channel blocker, or when the extracellular Ca²⁺ in the Ringer was replaced with equal molar EGTA. At IPL, the Ca²⁺ signal was also suppressed in a dose-dependent manner by brimonidine and other 2 receptor agonists, such as medetomidine. The suppressive action of brimonidine and medetomidine was completely blocked by classic 2 receptor antagonists, such as yohimbine, rauwolscine, and atipamezole. Interestingly, the 2 receptor agonists had no effect on the high K⁺ Ringer-elicited cytosolic Ca²⁺ signal at OPL. Blocking the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptor with D-AP5 attenuated this high K⁺–elicited Ca²⁺ signal by approximately 20% at IPL. D-AP5 had no effect on the Ca²⁺ signal at OPL.

CONCLUSIONS. These findings provide the first direct evidence of 2 receptor–mediated modulation of L-type Ca²⁺ channel activity in the CNS (the retina is part of the CNS). This 2 modulation appears to occur at the IPL but not at the OPL of the retina. These findings suggest that a physiological function of the retinal 2 system is the regulation of synaptic transmission at IPL and that brimonidine and other 2 agonists may protect RGCs under disease conditions by preventing abnormal elevation of cytosolic free Ca²⁺ either in RGCs, in their presynaptic cells, or in both.

This article has been cited by other articles:

				C.-J. Dong, Y. Guo, P. Agey, L. Wheeler, and W. A. Hare {alpha}2 Adrenergic Modulation of NMDA Receptor Function as a Major Mechanism of RGC Protection in Experimental Glaucoma and Retinal Excitotoxicity Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4515 - 4522. [Abstract] [Full Text] [PDF]