Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade.
Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade.
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DOI：
10.1113/jp271468
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Petersen OH
中科院分区：
文献类型：
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作者：
Gryshchenko O;Gerasimenko JV;Gerasimenko OV;Petersen OH
缓激肽可能在自身消化性疾病急性胰腺炎中发挥作用，但对其胰腺作用知之甚少。在这项研究中，我们研究了正常小鼠胰小叶中缓激肽引发的 Ca2+ 信号生成。我们发现胰腺腺泡 (PAC) 和星状细胞 (PSC) 之间的 Ca2+ 信号传导完全分离。病理生理学相关的缓激肽浓度始终通过 B2 受体在 PSC 中诱发 Ca2+ 信号，但从未在邻近的 PAC 中诱发 Ca2+ 信号，而胆囊收缩素始终在 PAC 中诱发 Ca2+ 信号，但从未在 PSC 中诱发 Ca2+ 信号。缓激肽引发的 Ca2+ 信号是由于最初 Ca2+ 从肌醇三磷酸敏感储备中释放，随后 Ca2+ 通过 Ca2+ 释放激活通道 (CRAC) 进入。 CRAC 阻滞剂可有效抑制 Ca2+ 进入阶段。 B2 受体阻断降低了胰腺炎促进剂引起的 PAC 坏死程度，因此我们得出结论，缓激肽通过对 PSC 的特定作用在急性胰腺炎中发挥作用。正常的胰腺星状细胞（PSC）被认为是静止的，只有在慢性胰腺炎和胰腺癌中才会被激活。然而，我们现在报告说，这些细胞在正常微环境中远非静止状态，而是能够产生大量的 Ca2+ 信号。我们比较了 PSC 中的 Ca2+ 信号传导和对其进行了深入研究的邻近腺泡细胞 (PAC)，发现即使在紧密相邻的 PAC 和 PSC 中，Ca2+ 信号传导也完全分离。缓激肽 (BK) 的浓度与体内自身消化性疾病急性胰腺炎中出现的血浆 BK 水平略有升高相对应，持续在 PSC 中引发大量 Ca2+ 信号，但从未在邻近的 PAC 中引发大量 Ca2+ 信号，而生理性 PAC 刺激性胆囊收缩素未能在 PSC 中引发 Ca2+ 信号。 BK 诱导的 Ca2+ 信号由 B2 受体介导，B2 受体阻断可防止急性胰腺炎药物引起的 PAC 坏死。 PSC 中最初的 Ca2+ 升高是由于肌醇三磷酸受体介导的内部储存释放，而持续阶段则取决于通过 Ca2+ 释放激活的 Ca2+ (CRAC) 通道的外部 Ca2+ 进入。 CRAC 通道抑制剂已被证明可以保护 PAC 免受诱发胰腺炎的药物造成的损害，因此也能抑制 PSC 中 Ca2+ 信号的产生，这可能有助于治疗急性胰腺炎。缓激肽可能在自身消化性疾病急性胰腺炎中发挥作用，但对其胰腺作用知之甚少。在这项研究中，我们研究了正常小鼠胰小叶中缓激肽引发的 Ca2+ 信号生成。我们发现胰腺腺泡 (PAC) 和星状细胞 (PSC) 之间的 Ca2+ 信号传导完全分离。病理生理学相关的缓激肽浓度始终通过 B2 受体在 PSC 中诱发 Ca2+ 信号，但从未在邻近的 PAC 中诱发 Ca2+ 信号，而胆囊收缩素始终在 PAC 中诱发 Ca2+ 信号，但从未在 PSC 中诱发 Ca2+ 信号。缓激肽引发的 Ca2+ 信号是由于最初 Ca2+ 从肌醇三磷酸敏感储备中释放，随后 Ca2+ 通过 Ca2+ 释放激活通道 (CRAC) 进入。 CRAC 阻滞剂可有效抑制 Ca2+ 进入阶段。 B2 受体阻断降低了胰腺炎促进剂引起的 PAC 坏死程度，因此我们得出结论，缓激肽通过对 PSC 的特定作用在急性胰腺炎中发挥作用。
Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin‐elicited Ca2+ signal generation in normal mouse pancreatic lobules. We found complete separation of Ca2+ signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca2+ signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca2+ signals in PACs, never elicited Ca2+ signals in PSCs. The bradykinin‐elicited Ca2+ signals were due to initial Ca2+ release from inositol trisphosphate‐sensitive stores followed by Ca2+ entry through Ca2+ release‐activated channels (CRACs). The Ca2+ entry phase was effectively inhibited by a CRAC blocker. B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis‐promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs. Normal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca2+ signals. We have compared Ca2+ signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca2+ signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto‐digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca2+ signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca2+ signals in PSCs. The BK‐induced Ca2+ signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca2+ rise in PSCs was due to inositol trisphosphate receptor‐mediated release from internal stores, whereas the sustained phase depended on external Ca2+ entry through Ca2+ release‐activated Ca2+ (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca2+ signal generation in PSCs and this may be helpful in treating acute pancreatitis. Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin‐elicited Ca2+ signal generation in normal mouse pancreatic lobules. We found complete separation of Ca2+ signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca2+ signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca2+ signals in PACs, never elicited Ca2+ signals in PSCs. The bradykinin‐elicited Ca2+ signals were due to initial Ca2+ release from inositol trisphosphate‐sensitive stores followed by Ca2+ entry through Ca2+ release‐activated channels (CRACs). The Ca2+ entry phase was effectively inhibited by a CRAC blocker. B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis‐promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs.