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**Nonclassic transmitters can be released at each level of the ANS** -------------------------------------------------------------------- In the 1930s, Sir Henry Dale first proposed that sympathetic nerves release a transmitter similar to epinephrine (now known to be norepinephrine) and parasympath...

**Nonclassic transmitters can be released at each level of the ANS** -------------------------------------------------------------------- In the 1930s, Sir Henry Dale 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 ]](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000136?scrollTo=%23t0010)). Thus, ACh and norepinephrine play important but not exclusive roles in autonomic control. 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](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0020) ), 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. CNS NEURONS PREGANGLIONIC AUTONOMIC NEURONS POSTGANG­LIONIC AUTONOMIC NEURONS VISCERAL AFFERENT NEURONS GANGLION INTERNEU­RONS ENTERIC NEURONS ------------------------------------------------------------------------- ------------- --------------------------------- ----------------------------------- --------------------------- ------------------------ ----------------- ACh X X **Monoamines** Norepinephrine X X X Epinephrine 5-hydroxytryptamine X X Dopamine X X **Amino acids** Glutamate X Glycine X Gamma-aminobutyric acid X **Neuropeptides** Substance P X X X X Thyrotropin-releasing hormone X Enkephalins X X X Neuropeptide Y X X X Neurotensin X X Neurophysin II X Oxytocin X Somatostatin X X X Calcitonin gene--related peptide X X X Galanin X X Vasoactive intestinal peptide X X Endogenous opioids X X Tachykinins (substance P, neurokinin A, neuropeptide K, neuropeptide γ) X Cholecystokinin X Gastrin-releasing peptide X **Nonclassical** NO X X ATP X X TABLE 14-3 Neurotransmitters Present Within the ANS 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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000136?scrollTo=%23p0715)). 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. **Two of the most unusual nonclassic neurotransmitters, ATP and nitric oxide, were first identified in the ANS** ---------------------------------------------------------------------------------------------------------------- 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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000136?scrollTo=%23p0195)). 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. **\ ** **ATP** ------- 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 P ~2~ **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 Ca ^2+^ permeability (see [p. 327 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000136?scrollTo=%23p0715)). In smooth muscle, ATP-induced depolarization can also activate voltage-gated Ca ^2+^ channels (see [pp. 189--190 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000070?scrollTo=%23p0590)) and thus lead to an elevation in \[Ca ^2+^ \] ~i~ and a rapid phase of contraction ( [Fig. 14-10](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0055) ). Norepinephrine, by binding to α ~1~ adrenergic receptors, acts through a heterotrimeric G protein (see [pp. 51--66 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000033?scrollTo=%23p0335)) to facilitate the release of Ca ^2+^ 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. Afbeelding met tekst, diagram, schermopname Automatisch gegenereerde beschrijving Figure 14-10 Cotransmission with ATP, norepinephrine, and neuropeptide Y in the ANS. In this example, stimulation of a postganglionic sympathetic neuron causes three phases of contraction of a vascular smooth-muscle cell. Each phase corresponds to the response of the postsynaptic cell to a different neurotransmitter or group of transmitters. In phase 1, ATP binds to a P2X purinoceptor (a ligand-gated cation channel) on the smooth-muscle cell, which leads to depolarization, activation of voltage-gated Ca ^2+ ^channels, increased \[Ca ^2+ ^\] ~i ~, and the rapid phase of contraction. In phase 2, norepinephrine, acting through an α ~1 ~adrenergic receptor and a G ~q ~/PLC/IP ~3 ~cascade, leads to Ca ^2+ ^release from internal stores and the second phase of contraction. In phase 3, when neuropeptide Y is present, it acts through a Y1 receptor to somehow cause an increase in \[Ca ^2+ ^\] ~i ~and thus produces the slowest phase of contraction. ER, endoplasmic reticulum; PLC, phospholi­pase C. **Nitric Oxide** ---------------- 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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000033?scrollTo=%23p0995)). 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](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0060) shows how a parasympathetic neuron may simultaneously release NO, ACh, and vasoactive intestinal peptide, each acting in concert to lower \[Ca ^2+^ \] ~i~ and relax vascular smooth muscle.  Figure 14-11 Action of NO in the ANS. Stimulation of a postganglionic parasympathetic neuron can cause more than one phase of relaxation of a vascular smooth-muscle cell, corresponding to the release of a different neurotransmitter or group of transmitters. The first phase in this example is mediated by both NO and ACh. The neuron releases NO, which diffuses to the smooth-muscle cell. In addition, ACh binds to M ~3 ~muscarinic receptors (i.e., GPCRs) on endothelial cells; this leads to production of NO, which also diffuses to the smooth-muscle cell. Both sources of NO activate guanylyl cyclase (GC) and raise \[cGMP\] ~i ~in the smooth muscle cell and contribute to the first phase of relaxation. In the second phase, which tends to occur more with prolonged or intense stimulation, the neuropeptide VIP (or a related peptide) binds to receptors on the smooth-muscle cell and causes delayed relaxation through an increase in \[cAMP\] ~i ~or a decrease in \[Ca ^2+ ^\] ~i ~.