An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
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DOI：
10.1016/j.neuropharm.2016.08.015
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发表时间：
2016-11
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;Blakely RD;Currie KPM
肾上腺嗜铬细胞（ACCs），交感神经系统的神经内分泌手臂，分泌的儿茶酚胺介导的生理反应的压力。虽然ACC不合成5-HT，但它们表达5-羟色胺转运体（SERT）。SERT的遗传变异与几种CNS疾病有关，但SERT / 5-HT在ACC中的作用仍不清楚。野生型小鼠的肾上腺中含有的5-HT丰度比肾上腺素低750倍，而在SERT−/−小鼠中，这一丰度降低了80%，而儿茶酚胺没有变化。碳纤维安培法表明，SERT调制的5-HT 1A受体的能力，抑制胞吐。5-HT减少了KCl在SERT−/−细胞和用SERT拮抗剂艾司西酞普兰处理的野生型细胞中诱发的电流尖峰（囊泡融合事件）的数量。5-HT_（1A）受体拮抗剂WAY_（100635）可阻断5-HT的这种抑制作用，而5-HT_（1B）受体激动剂CP_（93129）则不能。对电压门控性Ca 2+通道、K+通道或细胞内[Ca 2 +]处理无影响，表明5-HT受体募集非典型抑制机制。尖峰电荷和动力学没有被5-HT受体改变，但与野生型细胞相比，在SERT−/−细胞中减少。我们的数据揭示了SERT的一个新的作用，并表明肾上腺嗜铬细胞可能是一个以前未被认识到的枢纽交感神经应激反应的肾上腺素能控制。研究重点·交感神经系统中的肾上腺嗜铬细胞（ACC）表达SERT · ACCs含有少量5-HT，这是由于SERT摄取所致· SERT调节5-HT 1A受体抑制儿茶酚胺释放的能力· 5-HT 1A受体招募非典型机制，独立于Ca 2+或K+通道· ACCs可能是SSRI控制交感肾上腺应激的未被认识的枢纽
Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT / 5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT−/− mice this was reduced by ≈ 80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT−/− cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca2+ channels, K+ channels, or intracellular [Ca2+] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT−/− cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response. HIGHLIGHTS • Adrenal chromaffin cells (ACCs) in the sympathetic nervous system express SERT • ACCs contain small amounts of 5-HT due to uptake by SERT • SERT modulates the ability of 5-HT1A receptors to inhibit catecholamine release • 5-HT1A receptors recruit an atypical mechanism independent from Ca2+ or K+ channels • ACCs might be an unrecognized hub for control of sympathoadrenal stress by SSRIs
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