[Ca2+]i inhibition of Ca2+ release-activated Ca2+ influx underlies agonist- and thapsigargin-induced [Ca2+]i oscillations in salivary acinar cells.

Inhibition of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases by thapsigargin elicits [Ca2+]i oscillations in rat salivary gland (parotid) acinar cells which are similar to those activated by agonists but are nevertheless independent of inositol 1,4,5-trisphosphate (IP3) or IP3-sensitive Ca2+ stores (Foskett, J. K., Roifman, C. M., and Wong, D. (1991) J. Biol. Chem. 266, 2778-2782). Neither bafilomycin alone or together with monensin or chloroquine inhibited thapsigargin-induced [Ca2+]i oscillations, ruling out the involvement of vacuolar-type proton pumps or organellar acidity in the mechanisms underlying them. Acute inhibition of plasma membrane Ca(2+)-ATPase by 1 mM La3+ inhibited the decline of [Ca2+]i during the falling phase of the oscillation. Acute inhibition of plasma membrane Ca2+ influx by removal of extracellular Ca2+, membrane depolarization, or inorganic channel blockers immediately abolished oscillations, even when applied during the [Ca2+]i rising phase of the cycle. Ca2+ influx rate oscillated during [Ca2+]i oscillations, varying 1.5-13-fold during a cycle. Modification of the rate of Ca2+ influx, by titrating the extent of depletion of IP3-sensitive stores or manipulating extracellular [Ca2+], indicated that oscillations depended on a high rate of Ca2+ influx. In thapsigargin- or carbachol-treated cells which did not exhibit a sustained [Ca2+]i rise or [Ca2+]i oscillations, inhibition of Ca2+ influx activated plasma membrane Ca2+ permeability. Thus, agonist- and thapsigargin-induced [Ca2+]i oscillations in parotid acinar cells appear to be generated by plasma membrane-based mechanisms which involve periodic inactivation by [Ca2+]i of the Ca2+ release-activated Ca2+ influx pathway.