Maintaining the extracellular K+ concentration ([K+]o) between 15 and 60 mM induced oscillations in the intracellular Ca2+ concentration ([Ca2+]i) in rat submandibular acinar cells during stimulation with acetylcholine (ACh, 1 µM). These [Ca2+]i oscillations were also induced by 1 µM thapsigargin and were inhibited by 50 µM La3+, 1 µM Gd3+, or the removal of extracellular Ca2+, indicating that the [Ca2+]i oscillations were generated by store-operated Ca2+ entry (SOC). The frequency of the ACh-evoked [Ca2+]i oscillations increased from 0.8 to 2.3 mHz as [K+]o was increased from 15 to 50 mM. TEA (an inhibitor of K+ channels) also induced [Ca2+]i oscillations at [K+]o of 4.5 or 7.5 mM in ACh-stimulated cells. These data suggest that depolarization causes [Ca2+]i to oscillate in ACh-stimulated submandibular acinar cells. Pertussis toxin (PTX, an inhibitor of G proteins) caused [Ca2+]i to be sustained at a high level in ACh-stimulated cells at 25 mM or 60 mM [K+]o. This suggests that the [Ca2+]i oscillations are generated by a periodic inactivation of the SOC channels via PTX-sensitive G proteins, which are stimulated by depolarization. Moreover, in the presence of DBcAMP or forskolin which accumulated cAMP the frequency of the [Ca2+]i oscillations remained constant (approximately 1.2 mHz) when [K+]o was maintained in the range 25-60 mM. Based on these observations in ACh-stimulated submandibular acinar cells, we conclude that depolarization stimulates the PTX-sensitive G proteins, which inactivate the SOC channels periodically ([Ca2+]i oscillation), while hyperpolarization or PTX inhibits the G proteins, maintaining the activation of the SOC channels. Accumulation of cAMP is likely to modulate the PTX-sensitive G proteins. Experimental Physiology (2003) 88.3, 369-379.