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首页> 外文期刊>American Journal of Physiology >Interaction between bradykinin and natriuretic peptldes via RGS protein activation in HEK-293 cells
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Interaction between bradykinin and natriuretic peptldes via RGS protein activation in HEK-293 cells

机译：缓激肽与利钠肽之间的相互作用通过HEK-293细胞中的RGS蛋白活化

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摘要

In this study, the interaction of natriuretic peptides (NP) and bradykinin (BK) signaling pathways was identified by measuring membrane potential (V_m) and intracellu-lar Ca~(2+) using the patch-clamp technique and flow cytometry in HEK-293 cells. BK and NP receptor mRNA was identified using RT-PCR. BK (100 nM) depolarized cells activating bradykinin receptor type 2 (B2R) and Ca~(2+) -dependent Cl~ channels inhibitable by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 10 |xM). The BK-induced Ca~(2+) signal was blocked by the B_2R inhibitor HOE 140. [Des-Arg9]-bradykinin, an activator of BiR, had no effect on intra-cellular Ca~(2+) . NP [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin] depolarized HEK-293 cells inhibiting K~+ channels. ANP, urodilatin, BNP [binding to natriuretic peptide receptor (NPR)-A] and 8-bromo-(8-Br)-cGMP inhibited the BK-induced depolarization while CNP (binding to NPR-Bi) failed to do so. The inhibitory effect on BK-triggered depolarization could be reversed by blocking PKG using the specific inhibitor KT 5823. BK-stimulated depolarization as well as Ca~(2+) signaling was completely blocked by the phospholipase C (PLC) inhibitor U-73122 (10 nM). The inositol 1,4,5-trisphosphate receptor blocker 2-aminoethoxydiphenyl borate (2-APB; 50 muM) completely inhibited the BK-induced Ca~(2+) signaling. UTP, another activator of the PLC-mediated Ca~(2+) signaling pathway, was blocked by 13-13122 as well but not by 8-Br-cGMP, indicating an intermediate regulatory step for NP via PKG in BK signaling such as regulators of G-protein signaling (RGS) proteins. When RGS proteins were inhibited by CCG-63802 in the presence of BK and 8-Br-cGMP, cells started to depolarize again. In conclusion, as natural antagonists of the B_2R signaling pathway, NP may also positively interact in pathological conditions caused by BK.
机译：在这项研究中，利尿钠肽（NP）和缓激肽（BK）信号通路之间的相互作用是通过使用膜片钳技术和流式细胞仪检测HEK-中膜电位（V_m）和细胞内Ca〜（2+）来确定的293个细胞。使用RT-PCR鉴定BK和NP受体mRNA。 BK（100 nM）去极化的细胞激活2型缓激肽受体（B2R）和依赖Ca〜（2+）的Cl〜通道，该通道可被5-硝基-2-（3-苯基丙基氨基）苯甲酸（NPPB; 10 | xM）抑制。 BK诱导的Ca〜（2+）信号被B_2R抑制剂HOE 140阻断。[Des-Arg9]-缓激肽是BiR的激活剂，对细胞内Ca〜（2+）没有影响。 NP [心房利钠肽（ANP），脑利钠肽（BNP），C型利钠肽（CNP）和尿苷素]使HEK-293细胞去极化，抑制了K〜+通道。 ANP，urodilatin，BNP [与利钠肽受体（NPR）-A结合]和8-溴-（8-Br）-cGMP抑制BK诱导的去极化，而CNP（与NPR-Bi结合）则不能。可以通过使用特异性抑制剂KT 5823阻断PKG来逆转对BK触发的去极化的抑制作用。磷脂酶C（PLC）抑制剂U-73122完全阻断了BK刺激的去极化以及Ca〜（2+）信号传导（ 10 nM）。肌醇1,4,5-三磷酸酯受体阻滞剂2-氨基乙氧基二苯硼酸酯（2-APB; 50μM）完全抑制BK诱导的Ca〜（2+）信号传导。 UTP是PLC介导的Ca〜（2+）信号通路的另一种激活剂，也被13-13122阻断，但未被8-Br-cGMP阻断，表明NP经由PKG在BK信号传导中的中间调节步骤，例如调节剂。 G蛋白信号（RGS）蛋白的表达。当在BK和8-Br-cGMP存在下CCG-63802抑制RGS蛋白时，细胞再次开始去极化。总之，作为B_2R信号传导途径的天然拮抗剂，NP在由BK引起的病理状况中也可能正相互作用。

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