Cell type-specific modes of feedback regulation of capacitative calcium entry

The Ca2+-ATPase inhibitor, thapsigargin, activated Ca2+ entry into pancreatic acinar cells, a process known as capacitative calcium entry. In cells loaded with the calcium chelator BAPTA, the transient Ca2+ release was blunted and the rise of [Ca2+]i on readdition of Ca2+ was slowed. However, the steady-state [Ca2+]i due to Ca2+ entry was substantially augmented compared with control cells. This indicates that [Ca2+]i exerts a negative feedback on Ca2+ entry from a compartment buffered by BAPTA and separated from the bulk of cytoplasmic Ca2+. This interaction probably occurs close to the calcium channel where [Ca2+] is higher than in the bulk of the cytoplasm. In support of this interpretation, the slower Ca2+ chelator, EGTA, also blunted the release of Ca2+ and slowed the rise of the sustained [Ca2+]i phase but failed to augment steady-state [Ca2+]i. In contrast, Ca2+ entry in NIH 3T3 cells was characterized by a transient rise of [Ca2+]i that decays to near prestimulus levels. This decay in Ca2+ entry also results from negative feedback by Ca2+ because the decrease in Ca2+ entry was reversed by incubation in a Ca2+-deficient medium. However, unlike its effects in acinar cells, BAPTA neither augmented steady-state [Ca2+]i nor prevented the inactivation of entry. Rather, in BAPTA-loaded cells, [Ca2+]i failed to increase substantially suggesting that negative regulation by Ca2+ may occur at a site distinct from the cytoplasmic compartment and inaccessible to cytoplasmic BAPTA. These two distinct types of feedback behavior may indicate subtypes of store-operated calcium channels expressed in different cells or a single type of channel which is differentially regulated in a cell type-specific manner.