Modulation by Brain Natriuretic Peptide of GABA Receptors on Rat Retinal ON-Type Bipolar Cells
Modulation by Brain Natriuretic Peptide of GABA Receptors on Rat Retinal ON-Type Bipolar Cells
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DOI：
10.1523/jneurosci.3653-05.2006
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发表时间：
2006-01
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影响因子：
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通讯作者：
Yong-Chun Yu;L. Cao;Xiong-Li Yang
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作者：
Yong-Chun Yu;L. Cao;Xiong-Li Yang
利钠肽 (NP) 可以通过其相关受体 [NP 受体 (NPR)] 作为神经调节剂发挥作用。通过免疫细胞化学，我们发现 NPR-A 和 NPR-B 在大鼠视网膜 ON 型和 OFF 型双极细胞（BC）上大量表达，包括树突、体细胞和轴突末端。从分离的 ON 型 BC 中进行的全细胞记录进一步表明，脑利钠肽 (BNP) 抑制 GABAA 受体介导的 BC 电流，但不抑制 GABAC 受体介导的电流，而这种电流被 NPR-A 拮抗剂 anantin 阻断。 NPR-C 激动剂 c-ANF [des(Gln18, Ser19, Gln20, Leu21, Gly22)ANF4-23-NH2] 不会抑制 GABAA 电流。 BNP 对 GABAA 电流的影响通过与 pGC-A/B 拮抗剂 HS-142-1 预孵育而被消除，但通过应用 8-溴鸟苷-3',5'-环单磷酸来模拟。这些结果表明，NPR-A 激活引起的细胞内 cGMP 水平升高可能介导 BNP 效应。体内输注 cGMP 依赖性蛋白激酶 G (PKG) 抑制剂 KT5823 基本上阻断了 BNP 诱导的 GABAA 电流减少。此外，钙成像显示，BNP 导致细胞内钙显着升高，这可能是由于 PKG 导致细胞内储存的钙释放增加所致。 BNP 作用可被兰尼碱受体调节剂咖啡因、兰尼碱和钌红阻断，但不能被 IP3 受体拮抗剂肝素和 xestospongin-C 阻断。此外，应用内质网Ca2+-ATP酶阻滞剂毒胡萝卜素后，BNP作用被消除，并且钙调蛋白抑制剂W-7和卡咪唑鎓大大降低了BNP作用。因此，我们得出结论，BNP 增加从兰尼碱敏感性钙储存中释放的钙可能是通过刺激钙调蛋白而导致 ON 型 BC 中 BNP 引起的 GABAA 反应抑制的原因。
Natriuretic peptides (NPs) may work as neuromodulators through their associated receptors [NP receptors (NPRs)]. By immunocytochemistry, we showed that NPR-A and NPR-B were expressed abundantly on both ON-type and OFF-type bipolar cells (BCs) in rat retina, including the dendrites, somata, and axon terminals. Whole-cell recordings made from isolated ON-type BCs further showed that brain natriuretic peptide (BNP) suppressed GABAA receptor-, but not GABAC receptor-, mediated currents of the BCs, which was blocked by the NPR-A antagonist anantin. The NPR-C agonist c-ANF [des(Gln18, Ser19, Gln20, Leu21, Gly22)ANF4-23-NH2] did not suppress GABAA currents. The BNP effect on GABAA currents was abolished with preincubation with the pGC-A/B antagonist HS-142-1 but mimicked by application of 8-bromoguanosine-3′,5′-cyclomonophosphate. These results suggest that elevated levels of intracellular cGMP caused by activation of NPR-A may mediate the BNP effect. Internal infusion of the cGMP-dependent protein kinase G (PKG) inhibitor KT5823 essentially blocked the BNP-induced reduction of GABAA currents. Moreover, calcium imaging showed that BNP caused a significant elevation of intracellular calcium that could be caused by increased calcium release from intracellular stores by PKG. The BNP effect was blocked by the ryanodine receptor modulators caffeine, ryanodine, and ruthenium red but not by the IP3 receptor antagonists heparin and xestospongin-C. Furthermore, the BNP effect was abolished after application of the blocker of endoplasmic reticulum Ca2+-ATPase thapsigargin and greatly reduced by the calmodulin inhibitors W-7 and calmidazolium. We therefore conclude that the increased calcium release from ryanodine-sensitive calcium stores by BNP may be responsible for the BNP-caused GABAA response suppression in ON-type BCs through stimulating calmodulin.