Abstract
Cellular Ca2+ signals play a critical role in cell physiology and pathology. In most non-excitable cells, store-operated Ca2+ entry (SOCE) is an important mechanism by which intracellular Ca2+ signaling is regulated. However, few drugs can selectively modulate SOCE. 2-Aminoethoxydiphenyl borate (2APB) and its analogs (DPB162 and DPB163) have been reported to inhibit SOCE. Here, we examined the effects of another 2-APB analog, DPB161 on SOCE in acutely-isolated rat submandibular cells. Both patch-clamp recordings and Ca2+ imaging showed that upon removal of extracellular Ca2+ ([Ca2+]o=0), rat submandibular cells were unable to maintain ACh-induced Ca2+ oscillations, but restoration of [Ca2+]o to refill Ca2+ stores enable recovery of these Ca2+ oscillations. However, addition of 50 μM DPB161 with [Ca2+]o to extracellular solution prevented the refilling of Ca2+ store. Fura-2 Ca2+ imaging showed that DPB161 inhibited SOCE in a concentration-dependent manner. After depleting Ca2+ stores by thapsigargin treatment, bath perfusion of 1 mM Ca2+ induced [Ca2+]i elevation in a manner that was prevented by DPB161. Collectively, these results show that the 2-APB analog DPB161 blocks SOCE in rat submandibular cells, suggesting that this compound can be developed as a pharmacological tool for the study of SOCE function and as a new therapeutic agent for treating SOCE-associated disorders.
Highlights
Intracellular Ca2+ ([Ca2+]i) signals play critical roles in the modulation of cellular physiology and pathophysiology
In rat submandibular cells under the same experimental conditions, ACh-induced Ca2+ oscillatory responses stopped within minutes, and after washout of ACh with [Ca2+]o=0 solution for minutes, ACh still failed to induce any oscillatory responses (Figure 2B), suggesting an emptied intracellular Ca2+ store that was not refilled with extracellular Ca2+ in a store-operated Ca2+ entry (SOCE)-dependent manner
These results demonstrate that compared to pancreatic acinar cells, the response of rat submandibular cells to ACh stimulation is more dependent on Ca2+ entering through SOC channels to refill the Ca2+ store
Summary
Intracellular Ca2+ ([Ca2+]i) signals play critical roles in the modulation of cellular physiology and pathophysiology. In many non-excitable cells, intracellular Ca2+ signals respond to extracellular agonist stimulation in an oscillatory, rather than sustained, manner [1,2,3]. In 1986, Putney presented a model for capacitive calcium (Ca2+) entry conveying that depletion of endoplasmic reticulum-stored Ca2+ leads to activation of plasma membrane Ca2+ channels that mediate influx of Ca2+ from the extracellular space into cells [5], in a process called store-operated Ca2+ entry (SOCE). Ca2+ permeable channels on the plasma membrane [6], cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration and gene expression, demonstrating that SOC channels are important targets for normal cell function and a variety of diseases [7]. There is a need to develop new compounds for SOCE as pharmacological tools for investigation and as therapeutic agents for diseases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
