To investigate the mechanisms of oxidative injury of neurons and glia, we studied the photodynamic effect on isolated stretch receptor that consists of only two sensory neurons enwrapped by satellite glial cells. Photodynamic therapy (PDT), a potent inducer of oxidative stress, is a prospective method for destruction of brain tumors. PDT induced functional inactivation and necrosis of neurons, necrosis, apoptosis, and proliferation of glial cells. The roles of calmodulin, calmodulin-dependent kinase II, phospholipase C, protein kinases A and C, and phosphodiesterase in these processes were studied by using their inhibitors: fluphenazine, KN-93, D-609, H89, staurosporine, and papaverine, respectively. PDT-induced firing abolishment was enhanced by H89 or papaverine, whereas staurosporine acted oppositely. Fluphenazine or KN-93 reduced necrosis of neurons and glial cells. H89 enhanced necrosis of neurons, whereas staurosporine enhanced necrosis of glial cells. Inhibition of protein kinases A and C enhanced PDT-induced glial apoptosis. Photodynamic gliosis was prevented by KN-93 or staurosporine. These data indicate possible involvement of calmodulin and calmodulin-dependent kinase II in photoinduced necrosis of neurons and glia. Protein kinase C could protect glial cells from necrosis and apoptosis and participate in photoinduced gliosis and loss of neuronal activity. Protein kinase A maintained neuronal firing and protected neurons from photoinduced necrosis and glial cells from apoptosis. Phosphodiesterase reduced necrosis of photosensitized neurons and glia. Thus, Ca(2+)- and cAMP-mediated signaling pathways were involved in photooxidative injury of neurons and glia. Their pharmacological modulation may differently change the efficacy of photodynamic injury of neurons and glial cells.