Synaptic Physiology of the Autonomic Nervous System PDF

**Synaptic Physiology of the Autonomic Nervous System** ------------------------------------------------------- **The sympathetic and parasympathetic divisions have opposite effects on most visceral targets** ------------------------------------------------------------------------------------------...

**Synaptic Physiology of the Autonomic Nervous System** ------------------------------------------------------- **The sympathetic and parasympathetic divisions have opposite effects on most visceral targets** ------------------------------------------------------------------------------------------------ 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. 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. 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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000434?scrollTo=%23s0180)). 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. 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](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0040) ). 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. Afbeelding met buitenshuis, sneeuw, water, natuur Automatisch gegenereerde beschrijving Figure 14-7 Synapses of autonomic neurons with their target organs. Many axons of postganglionic neurons make multiple points of contact (varicosities) with their targets. In this scanning electron micrograph of the axon of a guinea pig postganglionic sympathetic neuron grown in tissue culture, the arrows indicate varicosities, or en passant synapses. **All preganglionic neurons---both sympathetic and parasympathetic---release acetylcholine and stimulate N 2 nicotinic receptors on postganglionic neurons** ------------------------------------------------------------------------------------------------------------------------------------------------------------ At synapses between postganglionic neurons and target cells, the two major divisions of the ANS use different neurotransmitters and receptors ( [Table 14-1](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0010) ). 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](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0045) ). Nicotinic receptors are ligand-gated channels (i.e., ionotropic receptors) with a pentameric structure (see [pp. 212--213 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000082?scrollTo=%23p0200)). [Table 14-2](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0015) summarizes some of the properties of nicotinic receptors. The nicotinic receptors on postganglionic autonomic neurons are of a molecular subtype (N ~2~ ) different from that found at the neuromuscular junction (N ~1~ ). Both are ligand-gated ion channels activated by ACh or nicotine. However, whereas the N ~1~ receptors at the neuromuscular junction (see [p. 212 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000082?scrollTo=%23p0200)) are stimulated by decamethonium and preferentially blocked by *d* -tubocurarine, the autonomic N ~2~ receptors are stimulated by tetramethylammonium but resistant to *d* -tubocurarine. When activated, N ~1~ and N ~2~ receptors are both permeable to Na ^+^ and K ^+^ . Thus, nicotinic transmission triggered by stimulation of preganglionic neurons leads to rapid depolarization of postganglionic neurons. SYMPATHETIC PREGANGLIONIC SYMPATHETIC POSTGANGLIONIC PARASYMPATHETIC PREGANGLIONIC PARASYMPATHETIC POSTGANGLIONIC -------------------------------- ----------------------------------------------------------- ---------------------------------------- ------------------------------------------- ------------------------------------------ Location of neuron cell bodies Intermediolateral cell column in the spinal cord (T1--L3) Prevertebral and paravertebral ganglia Brainstem and sacral spinal cord (S2--S4) Terminal ganglia in or near target organ Myelination Yes No Yes No Primary neurotransmitter ACh Norepinephrine ACh ACh Primary postsynaptic receptor Nicotinic Adrenergic Nicotinic Muscarinic Table 14.1  Figure 14-8 Major neurotransmitters of the ANS. In the case of the somatic neuron, the pathway between the CNS and effector cell is monosynaptic. The neuron releases ACh, which binds to N ~1 ~-type nicotinic receptors on the postsynaptic membrane (i.e., skeletal muscle cell). In the case of both the parasympathetic and sympathetic divisions, the preganglionic neuron releases ACh, which acts at N ~2 ~-type nicotinic receptors on the postsynaptic membrane of the postganglionic neuron. In the case of the postganglionic parasympathetic neuron, the neurotransmitter is ACh, but the postsynaptic receptor is a muscarinic receptor (i.e., GPCR) of one of five subtypes (M ~1 ~to M ~5 ~). In the case of most postganglionic sympathetic neurons, the neurotransmitter is norepinephrine. The postsynaptic receptor is an adrenergic receptor (i.e., GPCR) of one of two major subtypes (α and β). RECEPTOR TYPE AGONISTS [\*](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/tn0010) ANTAGONISTS G PROTEIN LINKED ENZYME SECOND MESSENGER ------------------------------------ ---------------------------------------------------------------------------------- ----------------------------------- ------------------- ------------------ ------------------ N ~1 ~nicotinic ACh ACh (nicotine, decamethonium) *d *-Tubocurarine, α-bungarotoxin --- --- --- N ~2 ~nicotinic ACh ACh (nicotine, TMA) Hexamethonium --- --- --- M ~1 ~/M ~3 ~/M ~5 ~muscarinic ACh ACh (muscarine) Atropine, pirenzepine (M ~1 ~) Gα ~q~ PLC IP ~3 ~and DAG M ~2 ~/M ~4 ~muscarinic ACh ACh (muscarine) Atropine, methoctramine (M ~2 ~) Gα ~i ~and Gα ~o~ Adenylyl cyclase ↓ \[cAMP\] ~i~ α ~1 ~adrenergic NE ≥ Epi (phenylephrine) Phentolamine Gα ~q~ PLC IP ~3 ~and DAG α ~2 ~adrenergic NE ≥ Epi (clonidine) Yohimbine Gα ~i~ Adenylyl cyclase ↓ \[cAMP\] ~i~ β ~1 ~adrenergic Epi \> NE (dobutamine, isoproterenol) Metoprolol Gα ~s~ Adenylyl cyclase ↑ \[cAMP\] ~i~ β ~2 ~adrenergic Epi \> NE (terbutaline, isoproterenol) Butoxamine Gα ~s~ Adenylyl cyclase ↑ \[cAMP\] ~i~ β ~3 ~adrenergic Epi \> NE (isoproterenol) SR59230A Gα ~s~ Adenylyl cyclase ↑ \[cAMP\] ~i~ D1 Dopamine (fenoldopam) LE 300 Gα ~s~ Adenylyl cyclase ↑ \[cAMP\] ~i~ D2 Dopamine (quinpirole) Thioridazine Gα ~i~ Adenylyl cyclase ↓ \[cAMP\] ~i~ Table 14-2 Signaling Pathways for Nicotinic, Muscarinic, Adrenergic, and Dopaminergic Receptors. DAG, diacylglycerol; Epi, epinephrine; NE, norepinephrine; PLC, phospholipase C; TMA, tetramethylammonium. \* Selective agonists are in parentheses. **All postganglionic parasympathetic neurons release ACh and stimulate muscarinic receptors on visceral targets** ----------------------------------------------------------------------------------------------------------------- All postganglionic *para* sympathetic neurons act through muscarinic ACh receptors on the postsynaptic target (see [Fig. 14-8](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0045) ). 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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000033?scrollTo=%23p0335))---also known as metabotropic receptors---that (1) stimulate the hydrolysis of phosphoinositide and thus increase \[Ca ^2+^ \] ~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 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000070?scrollTo=%23p0930)and [542 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000239?scrollTo=%23s0105)). Because they are mediated by second messengers, muscarinic responses, unlike the rapid responses evoked by nicotine receptors, are slow and prolonged. Muscarinic receptors exist in five different pharmacological subtypes (M ~1~ to M ~5~ ) 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 M ~1~ through M ~5~ 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.  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. 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 M ~1~ , M ~3~ , and M ~5~ on the one hand and M ~2~ and M ~4~ 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 M ~1~ , M ~3~ , and M ~5~ preferentially couple to Gα ~q~ and then to phospholipase C, with release of inositol 1,4,5-trisphosphate (IP ~3~ ) and diacylglycerol (see [p. 58 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000033?scrollTo=%23p0520)). On the other hand M ~2~ and M ~4~ preferentially couple to Gα ~i~ or Gα ~o~ to inhibit adenylyl cyclase and thus decrease \[cAMP\] ~i~ . **Most postganglionic sympathetic neurons release norepinephrine onto visceral targets** ---------------------------------------------------------------------------------------- Most postganglionic sympathetic neurons release **norepinephrine** (see [Fig. 14-8](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0045) ), which acts on target cells through adrenergic receptors. The sympathetic innervation of sweat glands is an exception to this rule. Sweat glands are innervated by sympathetic neurons that release ACh and act via muscarinic receptors (see [p. 571 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000240?scrollTo=%23s0240)). The adrenergic receptors are all GPCRs and are highly homologous to the muscarinic receptors (see [p. 341](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/s0080) ). Two major types of adrenergic receptors are recognized, α and β, each of which exists in multiple subtypes (e.g., α ~1~ , α ~2~ , β ~1~ , β ~2~ , and β ~3~ ). In addition, there are heterogeneous α ~1~ and α ~2~ receptors, with three cloned subtypes of each. [Table 14-2](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0015) lists the signaling pathways that are generally linked to these receptors. For example, β ~1~ receptors in the heart activate the G ~s~ heterotrimeric G protein and stimulate adenylyl cyclase, which antagonizes the effects of muscarinic receptors. Adrenergic receptor subtypes have a tissue-specific distribution. α ~1~ receptors predominate on blood vessels, α ~2~ on presynaptic terminals, β ~1~ in the heart, β ~2~ in high concentration in the bronchial muscle of the lungs, and β ~3~ in fat cells. This distribution has permitted the development of many clinically useful agents that are selective for different subtypes and tissues. For example, α ~1~ agonists are effective as nasal decongestants, and α ~2~ antagonists have been used to treat impotence. β ~1~ agonists increase cardiac output in congestive heart failure, whereas β ~1~ antagonists are useful antihypertensive agents. β ~2~ agonists are used as bronchodilators in patients with asthma and chronic lung disease. The adrenal medulla (see [pp. 1030--1034 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000501?scrollTo=%23p0505)) is a special adaptation of the sympathetic division, homologous to a postganglionic sympathetic neuron (see [Fig. 14-8](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0045) ). 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](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0015) ). In general, the α receptors have a greater affinity for norepinephrine, whereas the β receptors have a greater affinity for epinephrine. **Postganglionic sympathetic and parasympathetic neurons often have muscarinic as well as nicotinic receptors** --------------------------------------------------------------------------------------------------------------- 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. 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* (N ~2~ ) 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 14-9 *A *](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0050)shows a fast EPSP followed by a slow 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 14-9 *B *](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0050)*,* 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. 14-9 *C *](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0050)), 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. Figure 14-9 An example of dual nicotinic and muscarinic neurotransmission between sympathetic preganglionic and postganglionic neurons. **A, **Stimulation of a frog preganglionic sympathetic neuron releases ACh, which triggers a fast EPSP (due to activation of *nicotinic *receptors on the postganglionic sympathetic neuron), followed by a slow EPSP (due to activation of *muscarinic *receptors on the postganglionic neuron). **B, **In a rat sympathetic postganglionic neuron, the M current (mediated by a K ^+ ^channel) is normally active, hyperpolarizing the neuron. Thus, injecting current elicits only a single action potential. **C, **In the same experiment as in **B, **adding muscarine stimulates a muscarinic receptor (i.e., GPCR) and triggers a signal-transduction cascade that blocks the M current. One result is a steady-state depolarization of the cell. Injecting current now elicits a train of action potentials.