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嗜铬细胞中,L型钙通道在胞吐作用中依赖活动增强的作用受肾上腺素能信号调控。

An activity-dependent increased role for L-type calcium channels in exocytosis is regulated by adrenergic signaling in chromaffin cells.

作者信息

Polo-Parada L, Chan S-A, Smith C

机构信息

Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.

出版信息

Neuroscience. 2006 Dec 1;143(2):445-59. doi: 10.1016/j.neuroscience.2006.08.001. Epub 2006 Sep 8.

Abstract

Chromaffin cells of the adrenal medulla represent a primary output of the sympathetic nervous system. Their electrical stimulation evokes the fusion of large dense core granules with the cell membrane and the exocytic release of multiple transmitter molecules into the circulation. There the transmitters contribute to the regulation of basic metabolism of the organism. Under physiological activity, granule fusion and transmitter release are limited by activity-dependent Ca(2+) influx, entering through multiple isoforms of voltage-gated calcium channels. In this study we utilize perforated-patch voltage-clamp recordings and depolarize mouse chromaffin cells in situ with action potential-like waveforms to mimic physiological firing. We measure calcium influx through specific isoforms and measure cell capacitance as an index of granule fusion. Combining these approaches we calculate specific stimulus-secretion efficiencies for L-type, N-type, P/Q-type and R-type calcium channels under varied physiological activity levels. Current influx through all channel subtypes exhibited an activity-dependent depression. As expected P/Q-type channels, while responsible for modest Ca(2+) influx, are tightly coupled to catecholamine secretion under all conditions. We further find that stimulation designed to match sympathetic input under the acute stress response recruits L-type channels to a state of enhanced stimulus-secretion efficiency. N- and R-type channels do not undergo activity-dependent recruitment and remain loosely coupled to the secretion. Thus, only L-type channels exhibit activity-dependent changes in their stimulus-secretion function under physiological stimulation. Lastly, we show that treatment with the beta-adrenergic agonist, isoproterenol, specifically blocks the increase in the stimulus-secretion function of L-type channels. Thus, increased cell firing specifically enhances stimulus-secretion coupling of L-type Ca(2+) channels in chromaffin cells in situ. This mechanism is regulated by an adrenergic signaling pathway.

摘要

肾上腺髓质的嗜铬细胞是交感神经系统的主要输出部分。对其进行电刺激会促使大的致密核心颗粒与细胞膜融合,并将多种递质分子胞吐释放到循环系统中。在循环系统中,这些递质有助于调节机体的基础代谢。在生理活动状态下,颗粒融合和递质释放受到依赖于活动的Ca(2+)内流的限制,Ca(2+)通过多种电压门控钙通道亚型进入细胞。在本研究中,我们利用穿孔膜片钳电压钳记录技术,用类似动作电位的波形对原位小鼠嗜铬细胞进行去极化,以模拟生理放电。我们测量通过特定亚型的钙内流,并测量细胞电容作为颗粒融合的指标。结合这些方法,我们计算了在不同生理活动水平下L型、N型、P/Q型和R型钙通道的特定刺激-分泌效率。通过所有通道亚型的电流内流均表现出依赖于活动的衰减。正如预期的那样,P/Q型通道虽然只引起适度的Ca(2+)内流,但在所有条件下都与儿茶酚胺分泌紧密偶联。我们进一步发现,旨在模拟急性应激反应下交感神经输入的刺激会使L型通道进入刺激-分泌效率增强的状态。N型和R型通道不会发生依赖于活动的募集,并且与分泌的偶联仍然很弱。因此,只有L型通道在生理刺激下其刺激-分泌功能会发生依赖于活动的变化。最后,我们表明用β-肾上腺素能激动剂异丙肾上腺素处理可特异性阻断L型通道刺激-分泌功能的增强。因此,细胞放电增加会特异性增强原位嗜铬细胞中L型Ca(2+)通道的刺激-分泌偶联。这一机制受肾上腺素能信号通路的调控。

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