We recently published that SK3/KCa2.3 and SK4/KCa3.1 channels contribute to microglial activation and neurotoxicity via regulation of p38 MAPK activation; and were intrigued that two SK channels are involved in the same outcomes. Cloned SK channels are activated by similar rises in Ca2+; thus, we asked whether they are functionally coupled to different Ca2+ sources. Damaged neurons release ATP, a purinergic receptor ligand that activates microglia by raising intracellular Ca2+. Purinergic responses are mediated by ionotropic P2X or metabotropic P2Y receptors. Here, we stimulated MLS-9 cells (a microglia cell line that expresses both SK3 and SK4) with UTP to trigger P2Y-mediated responses; i.e., depletion of intracellular Ca2+ stores, and subsequent store operated Ca2+ entry (SOCE). In Fura-2 loaded cells, UTP evoked a rapid Ca2+ transient, followed by a second, more sustained rise due to SOCE. The second phase was decreased by the inhibitor 2-APB, which we recently showed blocks Ca2+ release-activated Ca2+ (CRAC) channels in microglia. In perforated-patch recordings, UTP activated a robust current, which was blocked by the SK4 inhibitor, TRAM-34 (but not by the SK3 blocker, apamin), and was therefore, SK4/KCa3.1. SK4 activation by UTP was also inhibited by 2-APB, suggesting that SOCE is required for, and coupled to, SK4 channel activation. SK4 activity was apparently needed for Ca2+ entry and store re-filling; the SK4 blocker, TRAM-34, accelerated the decay in internal Ca2+ after UTP, and reduced the amplitude of a second Ca2+ release from stores evoked by the SERCA pump inhibitor, thapsigargin. Our data support selective coupling of SK4 channels (but not SK3) to Ca2+ entry through SOCE/CRAC. Our current model is that SK4 activation maintains a hyperpolarized membrane potential that helps drive Ca2+ entry through CRAC, facilitating store refilling.