Autonomic Nervous System Physiology

The word efferent means “carrying messages away from the central nervous system (CNS).” The CNS communicates to the rest of the body through three major classes of efferent nerve fibers: (i) somatic, (ii) sympathetic preganglionic, and (iii) parasympathetic preganglionic. The first controls familiar voluntary muscle motor activity. The latter two belong to the autonomic nervous system (or simply, ANS), the subject of this chapter. The word autonomic implies involuntary, happening by itself. The agenda of these three efferent systems is different, crudely: (i) voluntary movement, (ii) fight & flight, and (iii) rest & These three classes of efferent nerve fibers have their cell bodies in the spinal cord or brain stem and send axons out as nerve bundles to the periphery. Such efferent nerve fibers all act by releasing the neurotransmitter acetylcholine (ACh) on their initial targets, so by definition they are called cholinergic (colored blue here). Here we focus on the neurotransmitters, receptors, and specialized cellular effector actions of ANS signaling.

(Unless otherwise noted, all figures are from:  Kandel ER, Schwartz JH, Jessell TM 2012, Siegelbaum SA, Hudspeth AJ. ‘Principles of Neural Science, 5th ed. McGraw-Hill, New York.)

Somatic nervous system efferents

Efferent somatic motoneurons innervate skeletal muscle forming a very large synapse: the neuromuscular junction (NMJ) or motor endplate. They excite action potentials in the muscle by opening depolariz- ing nicotinic ACh receptor ion channels (nAChRs) at the NMJ. Each skeletal muscle fiber is an obligatory follower of the motor axon that innervates it. Each presynaptic action potential propagating in a somatic motor axon elicits one postsynaptic action potential in the skeletal muscle fibers it innervates and one muscle twitch.

Autonomic nervous system efferents

Almost every organ of the body is innervated by the two autonomic peripheral systems called the sympathetic and parasympathetic nervous systems. In both, the innervation is via a two-neuron relay: first efferent preganglionic neurons and then peripheral postganglionic neurons. The efferent ANS nerve fibers that exit the CNS are called preganglionic because they release their ACh in the peripheral autonomic ganglia to excite the second postganglionic neurons that in turn innervate the peripheral targets of the ANS. The ANS efferent preganglionic nerve fibers form standard, focal, and fast nicotinic synapses on ANS postganglionic neurons. As it is for skeletal muscle, the ACh effect within the ganglion is depolarizing and excitatory, and the postganglionic neuron fires action potentials, acting mostly as a follower: Each preganglionic action potential elicits one or a few postganglionic action potentials in the second neuron. Thus, the somatic motor efferents and the ANS efferents share a common neurotransmitter (ACh) and act on quite similar (but genetically distinct) nicotinic receptors.

Autonomic postganglionic nerve fibers

We have emphasized that autonomic efferent signals are relayed in a second step by axons of post-ganglionic neurons to their final targets in a two-neuron efferent pathway (Figure 2)–we call this the “two-neuron rule.” The targets include glands, all muscles, the major organs, epithelia, and blood vessels. Instead of forming terminal focal synapses with point-to-point connections, the postganglionic neurons (the second neurons) of the ANS usually deliver neurotransmitters more diffusely throughout a target tissue by “sprinkled” release from numerous varicosities along the length of their axons. The varicosities are swellings–looking like beads on a string–that you could think of as sprinkler heads arranged along a water pipe. As is true of fast, focal synapses, the varicosities release their neurotransmitters in response to passing action potentials by calcium-dependent exocytosis from intracellular neurotransmitter vesicles concentrated in the varicosity. You should think of the actions of autonomic nervous system axons as broadly regulating groups of cells and tissues rather than as targeting a specific single cell.

An exception to the two-neuron rule

There is an exception to the two-neuron rule in the adrenal gland. The epinephrine-secreting chromaffin cells of the adrenal medulla are directly innervated by the “preganglionic” cholinergic efferent nerve rather than by a two-neuron pathway. However, loosely, one might regard the neuron-related, specialized secretory chromaffin cells as being like postganglionic neurons that deliver their epinephrine hormone/neurotransmitter by vesicular exocytosis, but now in endocrine fashion. They are round cells with no axons but release the hormone from the cell body to blood that circulates everywhere.

Sympathetic versus parasympathetic postganglionic neurotransmitter

We have emphasized the common features of postganglionic neurons. We now concentrate on the specialized properties that differentiate the postganglionic sympathetic from the postganglionic parasympathetic nerve fibers–with reference again to Figure 2.

•       Sympathetic postganglionic nerve fibers are adrenergic. They release norepinephrine (NE) by exocytosis from synaptic vesicles in their varicosities. (Colored green in Figure 2)

•       Parasympathetic postganglionic fibers are cholinergic. They release ACh by exocytosis from synaptic vesicles in their varicosities. (Colored blue in Figure 2.)

•       Both classes of postganglionic nerve fibers release additional mediators, sometimes called cotransmitters, in addition to NE or ACh. This may include neuropeptides and other small molecules such as ATP or nitric oxide. We do consider them later, but here we emphasize the principal neurotransmitters NE and ACh and their actions.

•       Exception:  At eccrine sweat glands, sympathetic postganglionic fibers release ACh instead of NE.

Receptors at each synapse

Nicotinic ACh receptors (nAChRs) are fast ligand-gated ion channels used at the cholinergic synapses on skeletal muscle endplates and at the synapses on all postganglionic neurons in autonomic ganglia. They are depolarizing (excitatory), nonselective cation channels that initiate action potentials. These nAChRs relay electrical excitation (action potentials) from the presynaptic neuron to a postsynaptic cell.

Distinguishing nicotinic and muscarinic ACh receptors

There are two major categories of AChRs: nicotinic (nAChR) and muscarinic (mAChR). Except that they both live in the plasma membrane and bind ACh, nicotinic and muscarinic receptors are quite different in structure, function, and pharmacology. Both have many isoforms (genes).

Nicotinic nAChRs are fast, ligand-gated cation channels opened directly by binding of ACh. Opening these channels can depolarize a cell to 0 mV. (Technically, being permeable to Na⁺ and K⁺, their reversal potential is around 0 mV.) Outside the central nervous system, nACHRs are located both at the skeletal neuromuscular junction (NMJ) and at synapses onto postganglionic neurons in all ANS ganglia and onto adrenal chromaffin cells. The nAChR isoforms (genes) expressed in nerve versus muscle are different, so it is possible to use drugs to block the neuronal and muscle receptors selectively. However, many nAChR pharmacological agents will affect both, including ACh, which is the natural agonist for both. The ACh binding sites of nAChRs are blocked by the paralytic drug curare and related compounds. The nicotinic name comes from the early discovery that nicotine and smoke from tobacco can activate these receptors as well. There are no nAChRs on cardiac muscle, smooth muscle, or on non-nerve/muscle tissue cells such as liver, kidney, epithelia, etc.

Muscarinic mAChRs are G-protein coupled receptors (GPCRs), not ion channels. They are located on the target tissues of parasympathetic innervation and at the sympathetic sweat gland—indeed on most cells of the body. There are five types, but the two primary receptor types to consider here are M2 and M3. All are inhibited by the drug atropine (an antagonist competing with ACh at the binding site) from deadly nightshade. Atropine does not affect nicotinic receptors.

M2 couples to Gαi.  It slows heart rate through both:

1)     activation of a K⁺ channel via Gβγ subunits, leading to hyperpolarization of pacemaker, and

2)     turning off the formation of the stimulatory cAMP second messenger through inhibiting adenylyl cyclase via Gαi.

M3 couples to Gαq.  The following three actions all result from the ability to elevate intracellular Ca²⁺ through Gq and the PLC/IP3 pathway.

•       Contracts smooth muscle.

•       Stimulates glands to secrete (including eccrine sweat glands).

•       Elevates nitric oxide (NO) production in endothelial cells leading to smooth muscle relaxation (vasodilation).

Synthesis and cycling of ANS neurotransmitters

We now review synthesis and degradation of the neurotransmitters E/NE and ACh (see also ANS Pharmacology sessions):

NE and E are catecholamines, members of the biogenic amine family. They are released from postganglionic varicosities, taken up again by a Na⁺/Cl⁻-coupled NE uptake transporter, and degraded by cytoplasmic monoamine oxidase (MOA).

You do NOT need to memorize their chemical structures.

•       Synthesis (Figure 4): The precursor tyrosine is taken up into varicosities by a Na⁺/tyrosine cotransporter. Cytosolic enzymes convert tyrosine to DOPA and then to dopamine.

•       Dopamine is transported into secretory vesicles.

•       Inside vesicles, dopamine is converted to NE.

•       In the adrenal gland, NE leaks out again to the cytosol where NE is methylated to form E (Figure 4), and E is re-transported into the giant secretory vesicles called “chromaffin granules” in the adrenal gland.

NE is normally released from vesicles by exocytosis, but NE also leaks from nerve into serum. This leak is increased if cytoplasmic monoamine oxidases (MAOs) are inhibited by MAO inhibitors (MAOIs).

ACh is an ester formed from choline and acetate (Figure 4). Choline and Acetyl-CoA are combined by choline acetyl transferase (ChAT) in the presynaptic terminal. ACh is then transported into secretory vesicles and released at varicosities and synaptic terminals. ACh is inactivated in the extracellular space by hydrolysis back to choline and acetate by the highly active extracellular enzyme acetylcholinesterase (AChE) present in all cholinergic tissues. The enzyme AChE is the target of nerve gases, such as CX, and organophosphate insecticides. Death is by accumulation of excess circulating ACh and, for humans, by exaggerated parasympathetic action. Choline is recycled by uptake into the nerve by a Na⁺-coupled cotransporter–conservation. There, choline acetyl transferase resynthesizes ACh. Of all the steps mentioned here, the AChE enzyme will be the most important one for you to remember now.