We have investigated the role of myelinating glia in events associated with propagation of the action potential at nodes of Ranvier using combinations of optical and electrophysiological recording methods. Calcium transients were observed in Schwann cells by fluorescent imaging of the nodal complex of fibers loaded with the calcium-sensitive dye fluo3-AM. To follow [Ca2+]i changes associated with neuronal activity at the node of Ranvier, nerves loaded with fluo3 were imaged during axonal activation using laser-scanning confocal microscopy. To elucidate sources of [Ca2+]i transients, we tested the effects of drugs known to alter [Ca2+]i. [Ca2+]i transients in Schwann cells were observed in response to axonal activation and these were subsequently blocked by ryanodine if ryanodine was present during a previous [Ca2+]i transient. Bath applications of caffeine induced [Ca2+]i transients which could be blocked by ryanodine. These findings indicate that calcium-activated calcium release occurs in Schwann cells in response to impulse activity.