Insulin secretion: a high-affinity Ca2+ sensor after all?
Insulin secretion: a high-affinity Ca2+ sensor after all?
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DOI：
10.1085/jgp.200409206
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发表时间：
2004-12
期刊：
影响因子：
--
通讯作者：
Rorsman P
中科院分区：
文献类型：
--
作者：
Barg S;Rorsman P
胰岛素通过大致密核心囊泡（LDCV）的Ca2+依赖性胞吐作用从胰岛β细胞分泌（Ammälä et al.，1993），这是一个由葡萄糖诱导的电活动触发的过程（Henquin和Meissner，1984）。响应于葡萄糖的逐步升高，胰岛素分泌遵循特征性的双相时程（咖喱等人，1968年）：在10 - 15分钟内完成的分泌的最初的短暂的第一阶段之后是缓慢发展和持续的第二阶段。据估计，分泌的第一阶段是由于每个β细胞快速释放总共40 - 80个LDCV，之后分泌以每分钟每个β细胞5个囊泡的速率进行（Rorsman和Renström，2003）。β细胞质膜中的Ca2+通道密度非常低，仅为嗜铬细胞中的约二十分之一（Barg et al.，2001年）。然而，巨噬细胞具有非常高的胞吐率。电容测量已经表明分泌可以以高达每秒500 LDCV的速率瞬时进行（Barg等人，2001年）。因此，已经提出，通过由Ca2+通道和胞吐蛋白组成的功能复合物的组装，β细胞胞吐有效地与Ca2+进入偶联（Wiser等人，1999），使得胞吐作用由在Ca2+通道的内口处发生的细胞质Ca2+浓度（[Ca2 +] i）的大幅增加触发（图1A）。根据这种情况，可以由电压钳去极化引起的胞吐速率需要将[Ca2 +] i升高几十微摩尔，如从使用笼状Ca2+的光解释放的实验估计的（Takahashi et al.，1997; Barg等人，2001年）。后者的实验表明，胞吐作用与[Ca2 +] i呈S形相关，Kd为20 μ M，希尔系数（n）高达5。相比之下，透化细胞的胰岛素分泌测量表明，胰岛素分泌在亚微摩尔[Ca 2 +] i时就已被激活（Yaseen等人，1982; Wollheim等人，1987; Okazaki等人，1994），并且在如此低的Ca2+浓度下也观察到电容增加（Proks等人，1996年）。事实上，后一种类型的测量表明，在低至几百纳摩尔的Ca2+浓度下，胞吐作用的速率比上述Ca2+依赖性所预期的速率高10，000倍。迄今为止，还没有解释这两个实验范式所示的胞吐作用的广泛不同的Ca2+依赖性。本期中出现的两项补充研究（Yang和Gillis，2004; Wan等人，2004）可以解释这个问题。最近，在两种类型的内分泌细胞中记录了能够响应于[Ca2 +] i的中度（低微摩尔）升高而释放的LDCV的小池：肾上腺嗜铬细胞（Yang等人，2002）和垂体促性腺激素（Zhu等，2002年）。这些囊泡的胞吐作用（称为高钙敏感池[HCSP]）与先前描述的低亲和力Ca2+依赖性胞吐作用平行进行。HCSP的释放是快速的（速率常数：10 - 100 s/1），在[Ca2 +] i 10 μ M时，HCSP的胞吐作用实际上比先前描述的快速初始组分更快。虽然这可能是不同途径的指示，但两种形式的胞吐都涉及SNARE蛋白。重要的是，HCSP的存在并不局限于内分泌细胞，并且还在视杆细胞突触中发现了HCSP，在视杆细胞突触中假定HCSP有助于响应的线性（Thoreson等人，2004).使用电容测量，Yang和Gillis（2004）和Wan等人（2005）使用电容测量。(2004...
Insulin is secreted from the ß-cells of the pancreatic islets by Ca2+-dependent exocytosis of large dense core vesicles (LDCVs)(Ämmälä et al., 1993), a process that is triggered by glucose-induced electrical activity (Henquin and Meissner, 1984). In response to a step elevation of glucose, insulin secretion follows a characteristic biphasic time course (Curry et al., 1968): an initial transient first phase of secretion, which is completed within 10–15 min, is followed by a slowly developing and sustained second phase. It has been estimated that the first phase of secretion is due to the rapid release of a total of 40–80 LDCVs per ß-cell, after which secretion proceeds at a rate of five vesicles per ß-cell per minute (Rorsman and Renström, 2003). The Ca2+ channel density in ß-cell plasma membranes is very low, only about one-twentieth of that in chromaffin cells (Barg et al., 2001). Yet, the ß-cell is capable of remarkably high rates of exocytosis. Capacitance measurements have suggested that secretion transiently may proceed at rates as high as 500 LDCV per second (Barg et al., 2001). It therefore has been proposed that the ß-cell exocytosis is efficiently coupled to Ca2+ entry via the assembly of a functional complex consisting of Ca2+ channels and exocytotic proteins (Wiser et al., 1999) so that exocytosis is triggered by the large increases in the cytoplasmic Ca2+ concentration ([Ca2+] i) occurring at the inner mouth of the Ca2+ channels (Fig. 1 A). In accordance with such a scenario, the rates of exocytosis that can be elicited by voltage-clamp depolarizations require elevation of [Ca2+] i by several tens of micromolar, as estimated from experiments using photolytic release of caged Ca2+(Takahashi et al., 1997; Barg et al., 2001). The latter experiments suggested that exocytosis is sigmoidally related to [Ca2+] i with a Kd of 20 μM and a Hill coefficient (n) as high as 5. By contrast, measurements of insulin secretion from permeabilized cells have indicated that insulin secretion is activated already at submicromolar [Ca2+] i (Yaseen et al., 1982; Wollheim et al., 1987; Okazaki et al., 1994) and capacitance increases have also been observed at such low Ca2+ concentrations (Proks et al., 1996). Indeed, the latter type of measurements indicate that exocytosis at Ca2+ concentrations as low as a few hundred nanomolar proceeds at rates 10,000-fold higher than that expected from the Ca2+ dependence quoted above. To date, there has been no explanation of the widely different Ca2+ dependencies of exocytosis indicated by these two experimental paradigms. Two complementary studies appearing in this issue (Yang and Gillis, 2004; Wan et al., 2004) may explain this conundrum. Recently, a small pool of LDCVs, capable of release in response to moderate (low micromolar) elevations of [Ca2+] i was documented in two types of endocrine cells: adrenal chromaffin cells (Yang et al., 2002) and pituitary gonadotropes (Zhu et al., 2002). Exocytosis of these vesicles (termed the highly calcium-sensitive pool [HCSP]) proceeds in parallel with the previously described low-affinity Ca2+-dependent exocytosis. Release of HCSP is rapid (rate constant: 10–100 sJ1) and at [Ca2+] i 10 μM, exocytosis of HCSP is actually faster than the rapid initial components previously described. Whereas this could be indicative of separate pathways, both forms of exocytosis involve SNARE proteins. Importantly, the existence of HCSP is not confined to endocrine cells and it has also been found in the rod photoreceptor synapse, where it was postulated to contribute to the linearity of the responses (Thoreson et al., 2004).Using capacitance measurements, Yang and Gillis (2004) and Wan et al.(2004 …
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影响因子：
5.5
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
16.2
作者：
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