Aim: SOCE is a process whereby depletion of intracellular Ca²⁺ stores causes the activation of plasma membrane Ca²⁺ channels. In nonexcitable cells, SOCE is predominantly controlled by the endoplasmic reticulum-resident Ca²⁺ sensing protein STIM1. However, it has recently been shown, that neuronal SOCE is regulated by the STIM1 homologue STIM2 (Berna-Erro et al., 2009). We aimed at clarifying the fundamental mechanisms of SOCE in cells of the CNS and at identifying useful pharmacological tools for manipulating SOCE in brain cells. Method: We investigated the effects of the known SOCE inhibitor 2-APB and the newly described cation channel blocker ACA in primary cultured cortical mouse neurons and microglial cells using fura-2 calcium imaging. Results: In microglia, we confirmed the suppression of SOCE by 50 mM 2-APB. ACA inhibited this Ca²⁺ entry with an IC₅₀ of 0.4 mM. In addition, we found an inhibitory effect of ACA on IP₃-dependent calcium release from intracellular stores. In contrast to the effects on microglia, ACA and 2-APB failed to inhibit SOCE in neurons. Instead, ACA induced a pronounced potentiation of calcium entry after store depletion (3.6-fold at 20 mM, 13-fold at 50 mM). Conclusion: From the opposite effects of ACA on SOCE in microglia and neurons we therefore suggest different molecular mechanisms for this calcium entry pathway in both cell types. Thus, ACA has emerged as a useful pharmacological tool for modulating SOCE in different cell types. Berna-Erro, A., Braun, A., Kraft, R., Kleinschnitz, C., Schuhmann, M., Stegner, D., Wultsch, T., Eilers, J., Meuth, S., Stoll, G., Nieswandt, B. 2009 Sci. Signal. 2, ra67