K+ channel modulation in rodent neurohypophysial nerve terminals by sigma receptors and not by dopamine receptors
K+ channel modulation in rodent neurohypophysial nerve terminals by sigma receptors and not by dopamine receptors
复制标题
DOI：
10.1111/j.1469-7793.1999.00391.x
复制
发表时间：
1999-06-01
影响因子：
5.5
通讯作者：
Jackson, MB
中科院分区：
文献类型：
--
作者：
Wilke, RA;Lupardus, PJ;Jackson, MB
1.σ受体结合多种化学上不相关的配体，包括喷他佐辛、阿扑吗啡（多巴胺受体激动剂）和氟哌啶醇（多巴胺受体拮抗剂）。虽然σ结合位点分布广泛，但其生理作用知之甚少。在这里，全末端膜片钳技术被用来证明sigma受体调节啮齿动物神经垂体中的K+通道.以前的工作表明，多巴胺4型（D-4）受体调节神经垂体K+电流，所以本研究初步测试多巴胺受体的作用。使用缺乏D-2、D-3或D-4受体的转基因小鼠进行的实验表明，PPHT和U101958（被认为对多巴胺受体具有选择性的配体）对K+电流的降低不是由多巴胺受体介导的。对U101958（一种与D-4受体结合的药物）的反应敏感性在野生型和D-4受体缺陷型小鼠中是相同的。用其他配体进行的实验揭示了与任何已知多巴胺受体不一致的药理学特征。此外，多巴胺本身（100 μ M）没有影响。因此，尽管许多假定的多巴胺受体配体的活性，多巴胺受体在神经垂体K+通道的调节中不起作用。由于关于多巴胺受体的阴性结果，并且由于已知此处使用的一些多巴胺受体配体也与σ受体结合，因此进行实验以测试σ受体的参与。在大鼠神经垂体中，σ受体配体SKF 10047、喷他佐辛和二甲苯基胍都以浓度依赖性方式可逆地抑制K+电流，氟哌啶醇和阿扑吗啡（与多巴胺和σ受体结合的配体）也是如此。这里测试的这些和其他配体的活性与报道的对σ受体的结合特异性相匹配。筛选十五种候选内源性σ受体配体，包括生物胺（例如多巴胺和血清素）、类固醇（例如孕酮）和肽（例如神经肽Y）对σ受体的活性。所有这些都没有效果。氟哌啶醇在所有电压下成比例地降低K+电流，而不改变激活和失活的电压依赖性。σ受体配体通过两种不同的K+通道（A通道和Ca 2+依赖性K+通道）抑制电流。在大鼠中，所有药物均成比例地降低了通过两个通道的电流，表明两个通道均由单个σ受体群体调节。相比之下，小鼠肽能神经末梢要么有两个对这些药物敏感的受体，要么有一个与离子通道功能差异偶联的受体。σ受体对电压激活的K+电流的抑制可能增强神经垂体分泌催产素和加压素。
1. Sigma receptors bind a diverse group of chemically unrelated ligands, including pentazocine, apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor antagonist). Although sigma binding sites are widely distributed, their physiological roles are poorly understood. Here, the whole-terminal patch-clamp technique was used to demonstrate that sigma receptors modulate K+ channels in rodent neurohypophysis.2. Previous work suggested that dopamine type 4 (D-4) receptors modulate neurohypophysial K+ current, so this study initially tested the role of dopamine receptors. Experiments using transgenic mice lacking D-2, D-3 or D-4 receptors indicated that the reduction of K+ current by PPHT and U101958 (ligands thought to be selective for dopamine receptors) is not mediated by dopamine receptors. The sensitivity of the response to U101958 (a drug that binds to D-4 receptors) was the same in both wild-type and D-4 receptor-deficient mice.3. Experiments with other ligands revealed a pharmacological signature inconsistent with any known dopamine receptor. Furthermore, dopamine itself (at 100 mu M) had no effect. Thus, despite the activity of a number of putative dopamine receptor ligands, dopamine receptors play no role in the modulation of neurohypophysial K+ channels.4. Because of the negative results regarding dopamine receptors, and because some of the dopamine receptors ligands used here are known to bind also to sigma receptors, experiments were conducted to test for the involvement of sigma receptors. In rat neurohypophysis the sigma receptor ligands SKF10047, pentazocine, and ditolylguanidine all reversibly inhibited K+ current in a concentration-dependent fashion, as did haloperidol and apomorphine (ligands that bind to both dopamine and sigma receptors). The activity of these and other ligands tested here matches the reported binding specificity for sigma receptors.5. Fifteen candidate endogenous sigma receptor ligands, including biogenic amines (e.g. dopamine and serotonin), steroids (e.g. progesterone), and peptides (e.g. neuropeptide Y), were screened for activity at the sigma receptor. All were without effect.6. Haloperidol reduced K+ current proportionally at all voltages without shifting the voltage dependence of activation and inactivation. Sigma receptor ligands inhibited current through two distinct K+ channels, the A-channel and the Ca2+-dependent K+ channel. In rat, all drugs reduced current through both channels proportionally, suggesting that both channels are modulated by a single population of sigma receptors. In contrast, mouse peptidergic nerve terminals either have two receptors which are sensitive to these drugs, or a single receptor that is differentially coupled to ion channel function.7. The inhibition of voltage-activated K+ current by sigma receptors mould be expected to enhance the secretion of oxytocin and vasopressin from the neurohypophysis.