This study is concerned with the transmitter-mediated regulation of the alpha(50 kDa) and beta(60 kDa) subunits of calcium calmodulin dependent protein kinase II (CamKII) in the adult rat retina. The level of antibody binding to the CamKII and the activity of CamKII were found to be increased after intravitreal injection of glutamate. Changes in the levels of the antibody-binding to the subunits of CamKII were observed in different subcellular fractions of the retina with a maximum response observed in crude synaptic membrane fractions. The glutamate mediated increases in CamKII were specific and blocked by 3,5-Dimethyl-1 adamantanamine; 3,5-Dimethylamantadine (Memantine), (+/-) 2-Amino-5-Phosphopentonic (AP-5) and 6-Cyano-7-Nitroquinoxaline-2,3-Dione (CNQX) but not with dl -2-Amino-3-Phosphono-Propionic (AP-3). The results indicate that the retinal neurotransmitter, glutamate, can regulate retinal CamKII activity through ionotropic but not metabotropic glutamate receptors. NMDA-receptors were found to be necessary but insufficient to stimulate CamKII. A model in which cooperative interaction between NMDA and non-NMDA glutamate receptors/ion channels is presented to explain the glutamate stimulated increases in CamKII activity in the retina.