查看Ch14 The Autonomic Nervous System的源代码

== 自主神经系统的突触生理学 ==
<b style=color:#f80>SYNAPTIC PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM</b>

=== 交感神经和副交感神经分支对大多数内脏目标具有相反的作用 ===
<b style=color:#0ae>The sympathetic and parasympathetic divisions have opposite effects on most visceral targets</b>

All innervation of skeletal muscle in humans is excitatory. In contrast, many visceral targets receive both inhibitory and excitatory synaptic inputs. These antagonistic inputs arise from the two opposing divisions of the ANS, the sympathetic and the parasympathetic.

人类骨骼肌的所有神经支配都是兴奋性的。相比之下，许多内脏靶标同时接受抑制性和兴奋性突触输入。这些对立的输入来自 ANS 的两个对立部分，即交感和副交感。


In organs that are stimulated during physical activity, the sympathetic division is excitatory and the parasympathetic division is inhibitory. For example, sympathetic input increases the heart rate, whereas parasympathetic input decreases it. In organs whose activity increases while the body is at rest, the opposite is true. For example, the parasympathetic division stimulates peristalsis of the gut, whereas the sympathetic division inhibits it.

在体力活动期间受到刺激的器官中，交感神经支是兴奋性的，而副交感神经支是抑制性的。例如，交感神经输入会增加心率，而副交感神经输入会降低心率。在身体处于静止状态时活动增加的器官中，情况正好相反。例如，副交感神经部门刺激肠道蠕动，而交感神经部门抑制肠道蠕动。


Although antagonistic effects of the sympathetic and parasympathetic divisions of the ANS are the general rule for most end organs, exceptions exist. For example, the salivary glands are stimulated by both divisions, although stimulation by the sympathetic division has effects different from those of parasympathetic stimulation (see p. 894). In addition, some organs receive innervation from only one of these two divisions of the ANS. For example, sweat glands, piloerector muscles, and most peripheral blood vessels receive input from only the sympathetic division.

尽管 ANS 交感神经和副交感神经分支的拮抗作用是大多数终末器官的一般规则，但也存在例外。例如，唾液腺受到两种部门的刺激，尽管交感神经部门的刺激与副交感神经刺激的效果不同（见第 894 页）。此外，一些器官仅从 ANS 的这两个分支之一获得神经支配。例如，汗腺、竖毛肌和大多数外周血管仅接收来自交感神经部的输入。


Synapses of the ANS are specialized for their function. Rather than possessing synaptic terminals that are typical of somatic motor axons, many postganglionic autonomic neurons have bulbous expansions, or varicosities, that are distributed along their axons within their target organ (Fig. 14-7). It was once believed that these varicosities indicated that neurotransmitter release sites of the ANS did not form close contact with end organs and that neurotransmitters needed to diffuse long distances across the extracellular space to reach their targets. However, we now recognize that many varicosities form synapses with their targets, with a synaptic cleft extending ~50 nm across. At each varicosity, autonomic axons form an “en passant” synapse with their end-organ target. This arrangement results in an increase in the number of targets that a single axonal branch can influence, with wider distribution of autonomic output.

ANS 的突触专门用于其功能。许多节后自主神经神经元不具有典型的体细胞运动轴突的突触末端，而是具有球状扩张或静脉曲张，这些扩张或静脉曲张分布在其靶器官内的轴突上（图 14-7）。曾经有人认为，这些静脉曲张表明 ANS 的神经递质释放位点不与终末器官形成密切接触，神经递质需要跨细胞外空间长距离扩散才能到达目标。然而，我们现在认识到许多静脉曲张与其靶标形成突触，突触裂隙延伸 ~50 nm。在每个静脉曲张处，自主神经轴突与其终末器官靶标形成一个“en passant”突触。这种安排导致单个轴突分支可以影响的目标数量增加，自主神经输出的分布更广。

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=== 所有节前神经元（包括交感神经和副交感神经）都会释放乙酰胆碱并刺激节后神经元上的 N2 烟碱受体 ===
<b style=color:#0ae>All preganglionic neurons—both sympathetic and parasympathetic—release acetylcholine and stimulate N2 nicotinic receptors on postganglionic neurons</b>

At synapses between postganglionic neurons and target cells, the two major divisions of the ANS use different neurotransmitters and receptors (Table 14-1). However, in both the sympathetic and parasympathetic divisions, synaptic transmission between preganglionic and postganglionic neurons (termed ganglionic transmission because the synapse is located in a ganglion) is mediated by acetylcholine (ACh) acting on nicotinic receptors (Fig. 14-8). Nicotinic receptors are ligand-gated channels (i.e., ionotropic receptors) with a pentameric structure (see pp. 212–213). Table 14-2 summarizes some of the properties of nicotinic receptors. The nicotinic receptors on postganglionic autonomic neurons are of a molecular subtype (N2) different from that found at the neuromuscular junction (N1). Both are ligand-gated ion channels activated by ACh or nicotine. However, whereas the N1 receptors at the neuromuscular junction (see p. 212) are stimulated by decamethonium and preferentially blocked by d-tubocurarine, N8-2 the autonomic N2 receptors are stimulated by tetramethylammonium but resistant to d-tubocurarine. When activated, N1 and N2 receptors are both permeable to Na+ and K+. Thus, nicotinic transmission triggered by stimulation of preganglionic neurons leads to rapid depolarization of postganglionic neurons.

在节后神经元和靶细胞之间的突触处，ANS 的两个主要分支使用不同的神经递质和受体（表 14-1）。然而，在交感神经和副交感神经分支中，节前神经元和节后神经元之间的突触传递（称为神经节传递，因为突触位于神经节中）是由作用于烟碱受体的乙酰胆碱 （ACh） 介导的（图 14-8）。烟碱受体是具有五聚体结构的配体门控通道（即离子型受体）（参见第 212-213 页）。表 14-2 总结了烟碱受体的一些特性。节后自主神经神经元上的烟碱受体属于与神经肌肉接头 （N1） 处发现的分子亚型 （N2） 不同。两者都是由 ACh 或尼古丁激活的配体门控离子通道。然而，神经肌肉接头处的 N1 受体（见第 212 页）受十甲铵刺激并优先被 d-tubocurarine 阻断，而自主神经 N2 受体受四甲基铵刺激，但对 d-tubocurarine 耐药。激活后，N1 和 N2 受体均能渗透 Na+ 和 K+。因此，由节前神经元刺激触发的烟碱传递导致节后神经元的快速去极化。

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=== 所有节后副交感神经元都释放 ACh 并刺激内脏靶标上的毒蕈碱受体 ===
<b style=color:#0ae>All postganglionic parasympathetic neurons release ACh and stimulate muscarinic receptors on visceral targets</b>

All postganglionic parasympathetic neurons act through muscarinic ACh receptors on the postsynaptic target (see Fig. 14-8). Activation of this receptor can either stimulate or inhibit function of the target cell. Cellular responses induced by muscarinic receptor stimulation are more varied than are those induced by nicotinic receptors. Muscarinic receptors are G protein–coupled receptors (GPCRs; see pp. 51–66)— also known as metabotropic receptors—that (1) stimulate the hydrolysis of phosphoinositide and thus increase [Ca2+]i and activate protein kinase C, (2) inhibit adenylyl cyclase and thus decrease cAMP levels, or (3) directly modulate K+ channels through the G-protein βγ complex (see pp. 197–198 and 542). Because they are mediated by second messengers, muscarinic responses, unlike the rapid responses evoked by nicotine receptors, are slow and prolonged.

所有节后副交感神经元都通过突触后靶标上的毒蕈碱 ACh 受体起作用（见图 14-8）。该受体的激活可以刺激或抑制靶细胞的功能。毒蕈碱受体刺激诱导的细胞反应比烟碱受体诱导的细胞反应更多样化。毒蕈碱受体是 G 蛋白偶联受体 （GPCR;见第 51-66 页）— 也称为代谢受体— （1） 刺激磷酸肌醇的水解，从而增加 [Ca2+]i 并激活蛋白激酶 C，（2） 抑制腺苷酸环化酶，从而降低 cAMP 水平，或 （3） 通过 G 蛋白 βγ 复合物直接调节 K+ 通道（参见第 197-198 页和第 542 页）。因为它们是由第二信使介导的，所以毒蕈碱反应与尼古丁受体诱发的快速反应不同，是缓慢而持久的。


Muscarinic receptors exist in five different pharmacological subtypes (M1 to M5) that are encoded by five different genes. All five subtypes are highly homologous to each other but very different from the nicotinic receptors, which are ligand-gated ion channels. Subtypes M1 through M5 are each stimulated by ACh and muscarine and are blocked by atropine. These muscarinic subtypes have a heterogeneous distribution among tissues, and in many cases a given cell may express more than one subtype. N14-3 Although a wide variety of antagonists inhibit the muscarinic receptors, none is completely selective for a specific subtype. However, it is possible to classify a receptor on the basis of its affinity profile for a battery of antagonists. Selective agonists for the different isoforms have not been available.

毒蕈碱受体存在于 5 种不同的药理学亚型 （M1 至 M5） 中，由 5 个不同的基因编码。所有五种亚型彼此高度同源，但与烟碱受体非常不同，烟碱受体是配体门控离子通道。M1 至 M5 亚型分别受到 ACh 和毒蕈碱的刺激，并被阿托品阻断。这些毒蕈碱亚型在组织之间具有异质性分布，在许多情况下，给定的细胞可能表达不止一种亚型。N14-3 尽管多种拮抗剂抑制毒蕈碱受体，但没有一种对特定亚型具有完全选择性。然而，可以根据受体对一组拮抗剂的亲和力特征对受体进行分类。目前还没有针对不同亚型的选择性激动剂。


A molecular characteristic of the muscarinic receptors is that the third cytoplasmic loop (i.e., between the fifth and sixth membrane-spanning segments) is different in M1, M3, and M5 on the one hand and M2 and M4 on the other. This loop appears to play a role in coupling of the receptor to the G protein downstream in the signal-transduction cascade. In general M1, M3, and M5 preferentially couple to Gαq and then to phospholipase C, with release of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (see p. 58). On the other hand M2 and M4 preferentially couple to Gαi or Gαo to inhibit adenylyl cyclase and thus decrease [cAMP]i (see p. 53).

毒蕈碱受体的分子特征是第三个细胞质环（即，在第五和第六跨膜段之间）一方面在 M1、M3 和 M5 上不同，另一方面在 M2 和 M4 上不同。该环似乎在信号转导级联反应中受体与下游 G 蛋白的偶联中发挥作用。通常，M1、M3 和 M5 优先与 Gαq 偶联，然后与磷脂酶 C 偶联，释放肌醇 1,4,5-三磷酸 （IP3） 和甘油二酯（见第 58 页）。另一方面，M2 和 M4 优先与 Gαi 或 Gαo 偶联以抑制腺苷酸环化酶，从而降低 [cAMP]i（见第 53 页）。

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=== 大多数节后交感神经元将去甲肾上腺素释放到内脏靶标上 ===
<b style=color:#0ae>Most postganglionic sympathetic neurons release norepinephrine onto visceral targets</b>

Most postganglionic sympathetic neurons release norepinephrine (see Fig. 15-8), which acts on target cells through adrenergic receptors. The sympathetic innervation of sweat glands is an exception to this rule. N14-4 Sweat glands are innervated by sympathetic neurons that release ACh and act via muscarinic receptors (see p. 571). The adrenergic receptors are all GPCRs and are highly homologous to the muscarinic receptors (see p. 341). Two major types of adrenergic receptors are recognized, α and β, each of which exists in multiple subtypes (e.g., α1, α2, β1, β2, and β3). In addition, there are heterogeneous α1 and α2 receptors, with three cloned subtypes of each. Table 14-2 lists the signaling pathways that are generally linked to these receptors. For example, β1 receptors in the heart activate the Gs heterotrimeric G protein and stimulate adenylyl cyclase, which antagonizes the effects of muscarinic receptors.

大多数节后交感神经元释放去甲肾上腺素（见图 15-8），它通过肾上腺素能受体作用于靶细胞。汗腺的交感神经支配是这个规则的一个例外[N14-4]。汗腺由交感神经元支配，交感神经元释放 ACh 并通过毒蕈碱受体发挥作用（见第 571 页）。肾上腺素能受体都是 GPCR，与毒蕈碱受体高度同源（见第 341 页）。肾上腺素能受体有两种主要类型，α 和 β，每种受体都存在于多个亚型中（例如，α1、α2、β1、β2 和 β3）。此外，还有异质性 α1 和 α2 受体，每种受体都有三个克隆亚型。表 14-2 列出了通常与这些受体相关的信号转导通路。例如，心脏中的 β1 受体激活 Gs 异源三聚体 G 蛋白并刺激腺苷酸环化酶，从而拮抗毒蕈碱受体的作用。


Adrenergic receptor subtypes have a tissue-specific distribution. α1 receptors predominate on blood vessels, α2 on presynaptic terminals, β1 in the heart, β2 in high concentration in the bronchial muscle of the lungs, and β3 in fat cells. This distribution has permitted the development of many clinically useful agents that are selective for different subtypes and tissues. For example, α1 agonists are effective as nasal decongestants, and α2 antagonists have been used to treat impotence. β1 agonists increase cardiac output in congestive heart failure, whereas β1 antagonists are useful antihypertensive agents. β2 agonists are used as bronchodilators in patients with asthma and chronic lung disease.

肾上腺素能受体亚型具有组织特异性分布。α1 受体在血管中占主导地位，α2 在突触前末梢，β1 在心脏中，β2 在肺支气管肌中高浓度，β3 在脂肪细胞中。这种分布允许开发许多临床上有用的药物，这些药物对不同的亚型和组织具有选择性。例如，α1 激动剂作为鼻减充血剂有效，α2 拮抗剂已用于治疗阳痿。β1 受体激动剂可增加充血性心力衰竭患者的心输出量，而 β1 受体拮抗剂是有用的降压药。β2 激动剂用作哮喘和慢性肺病患者的支气管扩张剂。


The adrenal medulla (see pp. 1030–1034) is a special adaptation of the sympathetic division, homologous to a postganglionic sympathetic neuron (see Fig. 14-8). It is innervated by preganglionic sympathetic neurons, and the postsynaptic target cells, which are called chromaffin cells, have nicotinic ACh receptors. However, rather than possessing axons that release norepinephrine onto a specific target organ, the chromaffin cells reside near blood vessels and release epinephrine into the bloodstream. This neuroendocrine component of sympathetic output enhances the ability of the sympathetic division to broadcast its output throughout the body. Norepinephrine and epinephrine both activate all five subtypes of adrenergic receptor, but with different affinities (see Table 14-2). In general, the α receptors have a greater affinity for norepinephrine, whereas the β receptors have a greater affinity for epinephrine.

肾上腺髓质（见第 1030-1034 页）是交感神经的特殊适应，与节后交感神经神经元同源（见图 14-8）。它由节前交感神经元支配，突触后靶细胞（称为嗜铬细胞）具有烟碱 ACh 受体。然而，嗜铬细胞并不具有将去甲肾上腺素释放到特定靶器官上的轴突，而是位于血管附近并将肾上腺素释放到血液中。交感神经输出的这种神经内分泌成分增强了交感神经部门将其输出广播到全身的能力。去甲肾上腺素和肾上腺素都激活肾上腺素能受体的所有五种亚型，但亲和力不同（见表 14-2）。一般来说，α 受体对去甲肾上腺素具有更大的亲和力，而 β 受体对肾上腺素的亲和力更大。

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=== 节后交感神经和副交感神经神经元通常具有毒蕈碱受体和烟碱受体 ===
<b style=color:#0ae>Postganglionic sympathetic and parasympathetic neurons often have muscarinic as well as nicotinic receptors</b>

The simplified scheme described in the preceding discussion is very useful for understanding the function of the ANS. However, two additional layers of complexity are superimposed on this scheme. First, some postganglionic neurons, both sympathetic and parasympathetic, have muscarinic in addition to nicotinic receptors. Second, at all levels of the ANS, certain neurotransmitters and postsynaptic receptors are neither cholinergic nor adrenergic. We discuss the first exception in this section and the second in the following section.

前面讨论中描述的简化方案对于理解 ANS 的功能非常有用。但是，此方案上还叠加了另外两层复杂性。首先，一些节后神经元，包括交感神经和副交感神经，除了烟碱受体外，还含有毒蕈碱。其次，在 ANS 的所有水平上，某些神经递质和突触后受体既不是胆碱能的，也不是肾上腺素能的。我们将在本节中讨论第一个异常，在下一节中讨论第二个异常。


If we stimulate the release of ACh from preganglionic neurons or apply ACh to an autonomic ganglion, many postganglionic neurons exhibit both nicotinic and muscarinic responses. Because nicotinic receptors (N2) are ligand-gated ion channels, nicotinic neurotransmission causes a fast, monophasic excitatory postsynaptic potential (EPSP). In contrast, because muscarinic receptors are GPCRs, neurotransmission by this route leads to a slower electrical response that can be either inhibitory or excitatory. Thus, depending on the ganglion, the result is a multiphasic postsynaptic response that can be a combination of a fast EPSP through a nicotinic receptor plus either a slow EPSP or a slow inhibitory postsynaptic potential (IPSP) through a muscarinic receptor. Figure 14-9A shows a fast EPSP followed by a slow EPSP.

如果我们刺激节前神经元释放 ACh 或将 ACh 应用于自主神经节，许多节后神经元会同时表现出烟碱和毒蕈碱反应。因为烟碱受体 （N2） 是配体门控离子通道，所以烟碱神经传递会导致快速、单相兴奋性突触后电位 （EPSP）。相反，由于毒蕈碱受体是 GPCR，因此通过这种途径进行的神经传递会导致较慢的电反应，这可能是抑制性的或兴奋性的。因此，根据神经节的不同，结果是多相突触后反应，可以是通过烟碱受体的快速 EPSP 加上通过毒蕈碱受体的慢速 EPSP 或慢速抑制性突触后电位 （IPSP） 的组合。图 14-9A 显示了一个快速 EPSP 后跟一个慢速 EPSP。


A well-characterized effect of muscarinic neurotransmission in autonomic ganglia is inhibition of a specific K+ current called the M current. The M current is widely distributed in visceral end organs, autonomic ganglia, and the CNS. In the baseline state, the K+ channel that underlies the M current is active and thereby produces slight hyperpolarization. In the example shown in Figure 14-9B, with the stabilizing M current present, electrical stimulation of the neuron causes only a single spike. If we now add muscarine to the neuron, activation of the muscarinic receptor turns off the hyperpolarizing M current and thus leads to a small depolarization. If we repeat the electrical stimulation in the continued presence of muscarine (see Fig. 14-9C), repetitive spikes appear because loss of the stabilizing influence of the M current increases the excitability of the neuron. The slow, modulatory effects of muscarinic responses greatly enhance the ability of the ANS to control visceral activity beyond what could be accomplished with only fast nicotinic EPSPs.

毒蕈碱神经传递在自主神经节中的一个明确特征的作用是抑制称为 M 电流的特定 K+ 电流。M 电流广泛分布于内脏终末器官、自主神经节和 CNS。在基线状态下，作为 M 电流基础的 K+ 通道是有效的，因此会产生轻微的超极化。在图 14-9B 所示的示例中，在存在稳定 M 电流的情况下，神经元的电刺激仅引起单个尖峰。如果我们现在将毒蕈碱添加到神经元中，毒蕈碱受体的激活会关闭超极化的 M 电流，从而导致小的去极化。如果我们在持续存在毒蕈碱的情况下重复电刺激（见图 14-9C），则会出现重复的尖峰，因为 M 电流稳定作用的丧失增加了神经元的兴奋性。毒蕈碱反应的缓慢调节作用大大增强了 ANS 控制内脏活动的能力，超出了仅使用快速烟碱 EPSP 所能完成的能力。

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=== 非经典发射机可以在 ANS 的每个级别释放 ===
<b style=color:#0ae>Nonclassic transmitters can be released at each level of the ANS</b>

In the 1930s, Sir Henry Dale N14-5 first proposed that sympathetic nerves release a transmitter similar to epinephrine (now known to be norepinephrine) and parasympathetic nerves release ACh. For many years, attention was focused on these two neurotransmitters, primarily because they mediate large and fast postsynaptic responses that can be easily studied. In addition, a variety of antagonists are available to block cholinergic and adrenergic receptors and thereby permit clear characterization of the roles of these receptors in the control of visceral function. More recently, it has become evident that some neurotransmission in the ANS involves neither adrenergic nor cholinergic pathways. Moreover, many neuronal synapses use more than a single neurotransmitter. Such cotransmission is now known to be common in the ANS. As many as eight different neurotransmitters may be found within some neurons, a phenomenon known as colocalization (see Table 13-1). Thus, ACh and norepinephrine play important but not exclusive roles in autonomic control.

在 1930 年代，亨利·戴尔爵士[N14-5] 首次提出交感神经释放类似于肾上腺素的递质（现在已知是去甲肾上腺素），副交感神经释放 ACh。多年来，人们的注意力都集中在这两种神经递质上，主要是因为它们介导了易于研究的大而快速的突触后反应。此外，有多种拮抗剂可用于阻断胆碱能和肾上腺素能受体，从而可以清楚地表征这些受体在控制内脏功能中的作用。最近，很明显 ANS 中的一些神经传递既不涉及肾上腺素能通路，也不涉及胆碱能通路。此外，许多神经元突触使用不止一种神经递质。现在已知这种共传在 ANS 中很常见。在某些神经元中可能发现多达 8 种不同的神经递质，这种现象称为共定位（见表 13-1）。因此，ACh 和去甲肾上腺素在自主神经控制中起着重要但并非排他性的作用。


The distribution and function of nonadrenergic, noncholinergic (NANC) transmitters are only partially understood. However, these transmitters are found at every level of autonomic control (Table 14-3), where they can cause a wide range of postsynaptic responses. These nonclassic transmitters may cause slow synaptic potentials or may modulate the response to other inputs (as in the case of the M current) without having obvious direct effects. In other cases, nonclassic transmitters have no known effects and may be acting in ways that have not yet been determined.

非肾上腺素能、非胆碱能 （NANC） 递质的分布和功能仅部分了解。然而，这些递质存在于自主神经控制的每个水平（表 14-3），它们可以引起广泛的突触后反应。这些非经典发射器可能会导致突触电位缓慢，或者可能会调制对其他输入的响应（如 M 电流的情况），而不会产生明显的直接影响。在其他情况下，非经典递质没有已知的影响，并且可能以尚未确定的方式发挥作用。

Although colocalization of neurotransmitters is recognized as a common property of neurons, it is not clear what controls the release of each of the many neurotransmitters. In some cases, the proportion of neurotransmitters released depends on the level of neuronal activity (see pp. 327–328). For example, medullary raphé neurons project to the intermediolateral cell column in the spinal cord, where they co-release serotonin, thyrotropin-releasing hormone, and substance P onto sympathetic preganglionic neurons. The proportions of released neurotransmitters are controlled by neuronal firing frequency: at low firing rates, serotonin is released alone; at intermediate firing rates, thyrotropin-releasing hormone is also released; and at high firing rates, all three neurotransmitters are released. This frequency-dependent modulation of synaptic transmission provides a mechanism for enhancing the versatility of the ANS.

尽管神经递质的共定位被认为是神经元的共同特性，但尚不清楚是什么控制了许多神经递质中每一种的释放。在某些情况下，释放的神经递质的比例取决于神经元活动的水平（参见第 327-328 页）。例如，髓质 raphé 神经元投射到脊髓的中间外侧细胞柱，在那里它们共同释放血清素、促甲状腺激素释放激素和 P 物质到交感神经节前神经元上。释放的神经递质的比例受神经元放电频率控制：在低放电速率下，血清素单独释放;在中等放电速率下，也会释放促甲状腺激素释放激素;在高放电速率下，所有三种神经递质都被释放。这种突触传递的频率依赖性调制提供了一种增强 ANS 多功能性的机制。

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=== 两种最不常见的非经典神经递质 ATP 和一氧化氮首先在 ANS 中被发现 ===
<b style=color:#0ae>Two of the most unusual nonclassic neurotransmitters, ATP and nitric oxide, were first identified in the ANS</b>

It was not until the 1970s that a nonadrenergic, noncholinergic class of sympathetic or parasympathetic neurons was first proposed by Geoffrey Burnstock and colleagues, who suggested that ATP might act as the neurotransmitter. This idea, that a molecule used as an intracellular energy substrate could also be a synaptic transmitter, was initially difficult to prove. However, it is now clear that neurons use a variety of classes of molecules for intercellular communication (see pp. 314–322). Two of the most surprising examples of nonclassic transmitters, nitric oxide (NO) and ATP, were first identified and studied as neurotransmitters in the ANS, but they are now known to be more widely used throughout the nervous system.

直到 1970 年代，Geoffrey Burnstock 及其同事才首次提出了一类非肾上腺素能、非胆碱能的交感神经或副交感神经神经元，他们认为 ATP 可能充当神经递质。这个想法，即用作细胞内能量基质的分子也可以是突触递质，最初很难证明。然而，现在很明显，神经元使用各种类别的分子进行细胞间通讯（参见第 314-322 页）。非经典递质的两个最令人惊讶的例子，一氧化氮 （NO） 和 ATP，首先在 ANS 中被确定和研究为神经递质，但现在已知它们在整个神经系统中得到更广泛的应用。


<b style=color:#f80>ATP</b> ATP is colocalized with norepinephrine in postganglionic sympathetic vasoconstrictor neurons. It is contained in synaptic vesicles, is released on electrical stimulation, and induces vascular constriction when it is applied directly to vascular smooth muscle. The effect of ATP results from activation of P2 purinoceptors on smooth muscle, which include ligand-gated ion channels (P2X) and GPCRs (P2Y and P2U). P2X receptors are present on autonomic neurons and smooth-muscle cells of blood vessels, the urinary bladder, and other visceral targets. P2X receptor channels have a relatively high Ca2+ permeability (see p. 327). In smooth muscle, ATP-induced depolarization can also activate voltage-gated Ca2+ channels (see pp. 189–190) and thus lead to an elevation in [Ca2+]i and a rapid phase of contraction (Fig. 14-10).

<b style=color:#f80>ATP</b> ATP 与去甲肾上腺素共定位于节后交感神经血管收缩神经元中。它包含在突触囊泡中，在电刺激下释放，当它直接应用于血管平滑肌时会诱导血管收缩。ATP 的影响是由于 P2 嘌呤受体对平滑肌的激活而产生的，平滑肌包括配体门控离子通道 （P2X） 和 GPCR （P2Y 和 P2U）。P2X 受体存在于自主神经元和血管、膀胱和其他内脏靶标的平滑肌细胞上。P2X 受体通道具有相对较高的 Ca2+ 通透性（参见第 327 页）。在平滑肌中，ATP 诱导的去极化还可以激活电压门控的 Ca2+ 通道（参见第 189-190 页），从而导致 [Ca2+]i 升高和快速收缩阶段（图 14-10）。


Norepinephrine, by binding to α1 adrenergic receptors, acts through a heterotrimeric G protein (see pp. 51–66) to facilitate the release of Ca2+ from intracellular stores and thereby produce a slower phase of contraction. Finally, the release of neuropeptide Y may, after prolonged and intense stimulation, elicit a third component of contraction.

去甲肾上腺素通过与 α1 肾上腺素能受体结合，通过异源三聚体 G 蛋白起作用（参见第 51-66 页），以促进 Ca2+ 从细胞内储存中释放，从而产生较慢的收缩阶段。最后，神经肽 Y 的释放，经过长时间和强烈的刺激，可能会引发收缩的第三个组成部分。

<b style=color:#f80>Nitric Oxide</b> In the 1970s, it was also discovered that the vascular endothelium produces a substance that induces relaxation of vascular smooth muscle. First called endothelium-derived relaxation factor, it was identified as the free radical NO in 1987. NO is an unusual molecule for intercellular communication because it is a short-lived gas. It is produced locally from L-arginine by the enzyme nitric oxide synthase (NOS; see pp. 66–67). The NO then diffuses a short distance to a neighboring cell, where its effects are primarily mediated by the activation of guanylyl cyclase. NOS is found in the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic divisions as well as in vascular endothelial cells. It is not specific for any type of neuron inasmuch as it is found in both norepinephrine- and ACh-containing cells as well as neurons containing a variety of neuropeptides. Figure 14-11 shows how a parasympathetic neuron may simultaneously release NO, ACh, and vasoactive intestinal peptide, each acting in concert to lower [Ca2+]i and relax vascular smooth muscle.

<b style=color:#f80>NO</b> 在 1970 年代，还发现血管内皮产生一种诱导血管平滑肌松弛的物质。它最初被称为内皮衍生的松弛因子，于 1987 年被确定为自由基 NO。NO 是一种不常见的细胞间通讯分子，因为它是一种短寿命气体。它是通过一氧化氮合酶 （NOS;见第 66-67 页） 从 L-精氨酸局部产生的。然后，NO 会扩散到邻近细胞，在那里其作用主要由鸟苷酸环化酶的激活介导。NOS 存在于交感神经和副交感神经分支的节前和节后神经元以及血管内皮细胞中。它对任何类型的神经元都没有特异性，因为它存在于含有去甲肾上腺素和 ACh 的细胞以及含有多种神经肽的神经元中。图 14-11 显示了副交感神经元如何同时释放 NO、ACh 和血管活性肠肽，每一种都协同作用以降低 [Ca2+]i 并放松血管平滑肌。

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