Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.
Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.
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DOI：
10.1111/jnc.14149
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发表时间：
2017-10
影响因子：
4.7
通讯作者：
Currie KPM
中科院分区：
文献类型：
--
作者：
Brindley RL;Bauer MB;Hartley ND;Horning KJ;Currie KPM
肾上腺嗜铬细胞（ACCs）是交感神经系统的神经内分泌分支，是生理应激反应的关键介质。从节前内脏神经释放的乙酰胆碱（ACh）激活嗜铬细胞上的烟碱乙酰胆碱受体（nAChR），引起膜去极化，打开电压门控Ca 2+通道（VGCC），以及儿茶酚胺和神经肽的胞吐。5-羟色胺转运蛋白（SERT）在ACC中表达，并与5-HT 1A受体相互作用以控制分泌。除了阻断SERT之外，一些选择性5-羟色胺再摄取抑制剂（SSRI）也是σ-1受体的激动剂，σ-1受体作为细胞内伴侣蛋白起作用并且可以移位到质膜以调节离子通道。因此，我们研究了SSRIs和其他sigma-1受体配体是否可以调节ACC中的刺激-分泌偶联。艾司西酞普兰和氟伏沙明（100 nM- 1μM）可逆性抑制nAChR电流。σ-1受体拮抗剂NE-100和BD-1047也阻断nAChR电流（在100 nM时阻断> 50%），如PRE-084（σ-1受体激动剂）。氟伏沙明和NE-100对nAChR电流的阻断作用不具有相加性，表明作用部位相同。VGCC电流不受药物的影响。无论是增加胞浆[Ca 2 +]或由此产生的儿茶酚胺分泌诱发的直接膜去极化旁路nAChRs的氟伏沙明或NE-100的改变。然而，由胆碱能激动剂卡巴胆碱引起的Ca 2+进入和儿茶酚胺分泌均被氟伏沙明或NE-100显著减少。总之，我们的数据表明，sigma-1受体不急性调节儿茶酚胺分泌。相反，SSRIs和其他σ-1受体配体抑制由胆碱能刺激引起的分泌，这是由于直接阻断经由nAChR的Ca 2+进入。σ-1受体是细胞内伴侣蛋白，其可以移位到质膜以调节各种离子通道和细胞功能。我们研究了几种sigma-1受体配体，包括氟伏沙明（一种选择性5-羟色胺再摄取抑制剂）对肾上腺嗜铬细胞分泌儿茶酚胺的影响。我们的数据表明，sigma-1受体不急性调节儿茶酚胺分泌。相反，sigma-1受体配体由于直接阻断Ca 2+通过尼古丁乙酰胆碱受体进入而抑制胆碱能刺激诱发的分泌。
Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter (SERT) is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking SERT, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100nM – 1μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈50% block at 100nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+] or the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs were altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation due to direct block of Ca2+entry via nAChRs. Sigma-1 receptors are intracellular chaperone proteins that can translocate to the plasma membrane to modulate various ion channels and cellular functions. We investigated the impact of several sigma-1 receptor ligands including fluvoxamine (a selective serotonin reuptake inhibitor) on catecholamine secretion from adrenal chromaffin cells. Our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, sigma-1 receptor ligands inhibited secretion evoked by cholinergic stimulation due to direct block of Ca2+entry via nicotinic acetylcholine receptors.
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