The release of catecholamines from adrenal chromaffin cells is known to be blocked by dihydropyridines, such as nitrendipine, and enhanced by others, such as BAY K8644. On the other hand, release from sympathetic neurons is predominantly insensitive to these agents. Release of [3H]norepinephrine from undifferentiated PC-12 pheochromocytoma cells resembles that from chromaffin cells in that it is extremely sensitive to dihydropyridines. Following differentiation, however, release of catecholamine becomes predominantly insensitive to both nitrendipine and BAY K8644. Under both growth conditions, release remains completely blocked by 3 mM Co2+ or by removal of Ca2+ from the release media.Dose-response curves to K+ show that following differentiation, cells become more sensitive, releasing transmitter at lower K+ concentrations. In contrast, depolarization-induced uptake of 45Ca2+ remains sensitive to dihydropyridines and shows similar sensitivity to K+ stimulation in both growth conditions. These results can be explained by invoking a model involving dihydropyridine-sensitive and -insensitive types of voltagesensitive calcium channels.The biochemical identification of ion channels has been greatly aided by the use of specific drugs or toxins that bind with high affinity to the channel protein (1-3). In the case of voltage-sensitive Ca2+ channels, there are several classes of drugs that have been shown to interact with voltage-sensitive Ca2+ channels in smooth, cardiac, and skeletal muscle (3). Of these agents, the dihydropyridines (DHP) are the most potent and specific. Some DHP (antagonists) block voltage-sensitive Ca2+ channels (4, 5) whereas others cause them to remain open for increased periods of time (agonists) (6, 7). Radioactive DHP have been used to label voltage-sensitive Ca2+ channels in muscle, endocrine cells, and neurons (3,(8)(9)(10)(11). The nervous system contains a high concentration of specific [3H]nitrendipine binding sites (11).In neurons and most endocrine cells, the influx of Ca2+ through voltage-sensitive Ca2+ channels acts as the initial trigger for release of hormones or neurotransmitters (stimulus/secretion coupling) (12). Thus, drugs that block voltage-sensitive Ca2+ channels should inhibit the evoked release of neurotransmitters. However, in spite of the fact that the nervous system contains many specific DHP "receptors", it has often been observed that such drugs do not alter neurotransmitter release (3). This has given rise to the suggestion that both drug-sensitive and -insensitive voltagesensitive Ca2+ channels exist (13). Indeed, a few reports have indicated that DHP-sensitive 45Ca2+ uptake (14) and neurotransmitter release (15, 16) can occur in some instances. Moreover, electrophysiological and fluorescence data have revealed the presence of both DHP-sensitive and -insensitive Ca2+ currents in neurons and other cells (17-19).The evoked release of catecholamines from adrenal chromaffin cells is highly sensitive to modulation by DHP (9). However, evoked release of transmitte...