ALPHA-2-ADRENERGIC AGONISTS SELECTIVELY ACTIVATE EXTRACELLULAR SIGNAL-REGULATED KINASES IN MULLER CELLS IN-VIVO

PURPOSE. alpha(2)-Adrenergic agonists have specific and selective effe cts on the retina to induce expression of basic fibroblast growth fact or and to protect photoreceptors. This work explores the signaling pat hway that mediates these effects. METHODS. alpha(2)-Adrenergic agonist s xylazine and clonidine were administered systemically to male adult Sprague-Dawley rats. The activation state of extracellular signal-regu lated kinases (ERKs) in the retina was assessed by immunoblot analysis , using antibodies that specifically recognize the dually phosphorylat ed forms of p44/p42 ERKs. Localization of phosphorylated ERKs was dete rmined by immunocytochemistry. RESULTS. Intramuscular injection of 6 m g/kg xylazine induced an increase in ERK phosphorylation in the retina within 30 minutes that lasted 3 hours. Xylazine induced ERK phosphory lation at 1 mg/kg and reached a maximum at 10 mg/kg. Injection of clon idine also induced ERK phosphorylation in the retina. Yohimbine, a spe cific alpha(2)-adrenergic antagonist, completely prevented the inducti on of ERK phosphorylation. Immunocytochemical studies showed that the increase in ERK phosphorylation occurred mainly in Muller cells. In th e brain, xylazine injection resulted in a decrease in ERK phosphorylat ion. CONCLUSIONS. Our results indicate that systemically administered alpha(2)-adrenergic agonists selectively activate ERKs in retinal Mull er cells. The induced activation of ERKs in Muller cells is probably o ne of the early events that result in photoreceptor protection. These results also indicate that Muller cells are unique in response to alph a(2)-adrenergic agonists and imply a role for Muller cells in alpha(2) -adrenergic agonist-induced photoreceptor protection.