We report in this study a 2-aminoethoxydiphenyl borate (2-APB) activated Ca 2+ pathway in NG115-401L (401L) neuronal cells bearing resemblance to hormonal and ryanodine receptor activated pathways. We observed that 2-APB, in contrast to much earlier work, did not inhibit store operated Ca 2+ channel (SOC) function, but rather induced potent Ca 2+ discharge responses that robustly activated SOC-mediated Ca 2+ influx. Further, these studies intriguingly revealed that the 2-APB-induced Ca 2+ release pathway likely couples conformationally to targets in the plasma membrane, as membrane permeabilization or actin perturbation abolished the ability of the compound to stimulate Ca 2+ signals. These findings suggest that conformationally sensitive complexes form between endoplasmic reticulum and plasma membrane components that not only regulate Ca 2+ influx, previously proposed as the conformational coupling hypothesis, but are also required to promote Ca 2+ release from intracellular stores. These observations further characterize the 401L neuronal cell line as having unique characteristics that may prove useful in gaining insight into the nature of the coupling mechanism linking Ca 2+ release to Ca 2+ influx.