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Autonomic Nervous System 2 & 3

Autonomic Nervous System 2 & 3

Autonomic Nervous System 2 & 3: Physiology & Molecular Mechanisms Margaret C. Biber, D. Phil.

OBJECTIVES:

Please note that these objectives pertain to ANS lectures I-IV.

At the end of these lectures you should know and understand the following material:

1. The relationship between the organization of the sympathetic and parasympathetic divisions of the ANS to their overall physiological effects. 2. Anatomical and functional differences between the skeletal and autonomic neuroeffector junctions. 3. Transmitters used at ganglionic and neuroeffector junctions and highlights of the transmitter life cycle: Storage, release, biological inactivation, metabolism and de novo synthesis for (Ach), (NE) and the hormone, epinephrine (EPI). 4. types for Ach and the catecholamines, NE and EPI and their effects. 5. The of other transmitters/mediators including ATP, NO and peptides. 6. The organization of autonomic reflexes. 7. The overall physiological effects of the parasympathetic and sympatho-adrenal systems and the receptor types that mediate the responses.

Reading: Berne, Levy, Koeppen and Stanton: Physiology, 5th edition. 2004; Ch. 11, Pages 206-215 –Table 11-1 is too detailed. Use Table in handout. Costanzo: Physiology, 2006 Ch. 2, Pages 45-64

Note: Please follow the version in the handout wherever discrepancies exist between the textbooks and the handout.

LECTURES II & III OUTLINE

COMPARISON OF SYMPATHO-ADRENAL & PARASYMPATHETIC Sympatho-adrenal: diffuse targets expenditure of energy Parasympathetic: discrete targets conservation of energy MOLECULAR BASIS FOR ACTIONS OF ANS: TRANSMITTERS: Identity & sites of release Life cycle of ACh Life cycle of NE in sympathetic varicosity Evoked release of small transmitters and peptides Adrenal medulla: storage, release, synthesis and metabolism Pheochromocytoma RECEPTORS Nicotinic & Muscarinic Parasympathetic effects Alpha & Beta Sympatho-adrenal effects Summary of effects of sympathoadrenal and parasympathetic on target tissues (Table 1)

COMPARISON OF SYMPATHETIC AND PARASYMPATHETIC

The ANS maintains man and adapts him to his environment but the sympathetic and parasympathetic nervous systems have rather different roles:

• The sympathetic nervous system mobilizes the body for activity and, in the extreme case, in conjunction with the adrenal gland, allows the body to handle threatening situations (FIGHT or FLIGHT). • The parasympathetic plays a restorative role and conserves energy. • Differences exist in the targets of these two systems:

The sympathetic innervates widely distributed systems. The parasympathetic exerts a more discrete control.

It is easier to remember the actions of these two systems at the level of individual organs and tissues if one first has an understanding of their overall function and can then relate this to their organization.

SYMPATHETIC NERVOUS SYSTEM

ƒ Diffuse Target Tissues • sweat glands • of blood vessels supplying skeletal muscle, skin • smooth muscle of hair follicles

In man, these target tissues do not have any parasympathetic innervation. The sympathetic has excitatory actions on these tissues. Consequently, it regulates:

• (blood vessels supplying the skeletal muscle are especially important; the ANS innervation to heart also contributes) • the distribution of blood among tissues and within tissues • body temperature (cutaneous blood vessels; sweat glands) Figure 1.

ƒ STRESS RESPONSE

Together with the adrenal gland, the sympathetic NS mobilizes the body to handle threatening situations -- the fight or flight reaction. The effects of the sympatho- adrenal enable the body to undertake severe physical exertion. The activity of organs that are nonessential or counterproductive is inhibited. Targets of sympatho-adrenal action include:

• Cardiovascular system: o redistribution of blood, e.g., flow of blood to the skin and mesentery is dramatically reduced, flow to skeletal muscle is enhanced. o increase in cardiac output • Respiratory system: o relaxation of muscles of trachea and bronchi • Digestive system: o inhibition of motility and secretions • Metabolism: o mobilization of glucose, o increased lipolysis, o increase in basal metabolic rate

PARASYMPATHETIC NERVOUS SYSTEM

ƒ Conservation/Replenishment of Energy Supplies, Maintenance of the Organism. ƒ Discrete Control of Individual Target Tissues

Examples of parasympathetic regulation include:

• excitatory effects on the (increases motility and secretory activity in sequential fashion as digestion proceeds) • stimulation of glandular secretions (but sympathetic controls sweat glands) • slowing of the heart • control of diameter by the pupillary light reflex (regulates the amount of light falling on the retina) • accommodation of the lens for near vision • voiding the (micturition)

SUMMARY OF SYMPATHO-ADRENAL AND PARASYMPATHETIC EFFECTS BY TARGET TISSUE HEART : sympatho-adrenal has excitatory effects: it increases the rate of beating and the force of contraction parasympathetic is inhibitory, slowing heart rate

SMOOTH sympatho-adrenal can excite or inhibit smooth muscle MUSCLE: (adrenal medulla relaxes bronchial smooth muscle; sympathetic constricts vascular smooth muscle). parasympathetic excites most of the smooth muscle it innervates (e.g GI tract; urinary bladder)

GLANDS: parasympathetic stimulates glandular secretions (sympathetic stimulates sweat glands)

METABOLIC EFFECTS: mediated by the sympatho-adrenal system

To understand the basis for the different actions of the sympathetic and parasympathetic NS on their target organs requires an understanding of the molecular mechanisms that mediate these effects, including the transmitters released at the neuroeffector junction, and the receptors with which they interact.

Figure 2. AUTONOMIC NERVOUS SYSTEM: TRANSMITTERS

MOLECULAR BASIS FOR PHYSIOLOGICAL ACTIONS OF ANS

TRANSMITTERS AND SITES OF RELEASE (FIG. 2)

ƒ Acetylcholine (Ach) • : Terminals of both parasympathetic and sympathetic preganglionic release ACh • Neuro-Effector Junction: Terminals of parasympathetic postganglionic nerves release ACh onto the target effector tissues Terminals of sympathetic postganglionic nerves that supply the sweat glands that cover the body (generally distributed sweat glands) also release ACh.

ƒ Norepinephrine (NE) • Neuro-Effector Junction: Terminals of sympathetic postganglionic nerves release the catecholamine, NE onto target effector tissues, (except in the case of generally distributed sweat glands).

HORMONE RELEASE from adrenal medulla

ƒ Epinephrine (EPI), a catecholamine (CA) closely related to NE, is the principal CA released into the blood stream along with small amounts of NE.

ƒ The methyl substituent on the amine group accounts for EPI’s characteristic properties that distinguish it from NE.

LIFE CYCLE OF TRANSMITTERS/HORMONES: ACETYLCHOLINE

• ACh is stored in small clear (agranular) vesicles that also contain high concentrations of ATP (FIG 3). • A few large dense cored vesicles that store peptides such as vasoactive intestinal peptide (VIP) are also present. Peptide is released with high frequency stimulation and augments the effects of Ach on the target organ. • Released ACh interacts with receptors and is rapidly destroyed within msecs of its release through metabolic breakdown by acetylcholinesterase (FIG 3), one of the most rapidly acting in the body. • Inhibition of acetylcholinesterase potentiates and prolongs the effects of ACh in the ANS. • ACh supplies are replenished by acetyltransferase from choline and acetylCo A. There is a sodium dependent choline uptake mechanism into the terminal.

Figure 3. CHOLINERGIC NERVE VARICOSITY

NOREPINEPRINE (FIG 4)

• NE in sympathetic postganglionic nerve terminal varicosities is stored mostly in small dense cored vesicles that contain NE, ATP and beta hydroxylase (converts dopamine to NE)(FIG 4). Some large dense cored vesicles contain enkephalin as well as all the other components. • A separate population of large dense cored vesicles stores peptides such as neuropeptide Y that is released with high frequency stimulation and enhances the effect of NE. • Released NE is biologically inactivated by by a sodium dependent transporter molecule present in the membrane of postganglionic sympathetic nerve terminal varicosities. • Once inside the sympathetic nerve terminal, NE is either taken up into a storage vesicle for subsequent release or metabolized. • Inhibition of reuptake (e.g. with ) potentiates the effects of NE. • Supplies of NE are maintained by reuptake and by synthesis of new transmitter (see below).

Figure 4. POSTGANGLIONIC SYMPATHETIC NERVE VARICOSITY

Figure 5. EVOKED RELEASE OF TRANSMITTER

EVOKED RELEASE OF TRANSMITTER

• Requires calcium entry into the nerve terminal and occurs by . • Involves the same quantal release mechanism described for the motor nerve at the skeletal NMJ (see Dr DeSimone’s notes), BUT the probability of release of quanta is much lower than for somatic motor nerves and hence the amount of transmitter released by a single is less. • Substances stored in the same vesicle are released together. For example, ATP and NE are coreleased from NE storing vesicles of postganglionic sympathetic nerves. • Peptides stored in separate large dense cored vesicles (e.g. VIP) are only released in response to high frequency stimulation. • The neuronal firing pattern (e.g. low frequency versus higher frequency of action potentials) determines the mixture of transmitters released and hence the nature of the chemical signal received by the target tissue.

THE ADRENAL MEDULLA

• In the adrenal medulla, EPI (or NE) is stored in large dense cored vesicles. These vesicles also contain: o high concentrations of ATP o peptides, leu and met enkephalin o high MW proteins including: an , dopamine-beta-hydroxylase highly acidic proteins, the chromogranins

• In response to splanchnic nerve activity, CA and other vesicle contents are released directly into the blood stream from the adrenal medulla and act on targets at a distance. • The half life of circulating EPI is approximately 10 secs. To produce a prolonged effect, the adrenal must continue to release amine. • Stores of EPI (and NE) are replenished by resynthesis. The steps in CA synthesis are as follows (Figure 6):

Figure 6. SYNTHESIS AND STORAGE OF CATECHOLAMINES

• Substrate, tyrosine, an aromatic , is made by hydroxylation of phenylalanine by a liver enzyme, PHENYLALANINE HYDROXYLASE. (Lack of phenylalanine hydroxylase causes phenylalanine to accumulate in the blood stream. An elevated blood level of phenylalanine interferes with uptake of other amino acids into the CNS and, if untreated, produces mental retardation. The disorder is known as phenylketonuria (PKU), and is treated by dietary restriction of phenylalanine). Tyrosine made from phenylalanine is taken up from the circulation by sympathetic nerve terminals or adrenal chromaffin cells. • TYROSINE HYDROXYLASE converts tyrosine to dopa (3,4- dihydroxyphenylalanine). This enzyme reaction is highly regulated and hence is rate limiting for CA synthesis. Tyrosine hydroxylase activity increases dramatically with nerve stimulation. The increase in activity involves rapid phosphorylation by protein kinase A. • Prolonged stimulation of the sympatho-adrenal system (e.g by severe stress) increases the levels of tyrosine hydroxylase protein. This adaptive response is critical for maintaining NE levels in sympathetic nerves and EPI in the adrenal medulla.

• Several additional steps follow the hydroxylation of tyrosine: • Dopa is decarboxylated to dopamine by the cytoplasmic enzyme DOPA DECABOXYLASE (also called AROMATIC AMINO ACID DECARBOXYLASE) • Dopamine is pumped into the storage vesicle where it is converted to NE by DOPAMINE-BETA-HYDROXYLASE. Synthesis stops here in sympathetic postganglionic nerve terminals. • EPI is formed by methylation of NE on the amino group by PHENYLETHANOLAMINE-N-METHYL TRANSFERASE (PNMT). • PNMT is a cytoplasmic enzyme. NE leaves the storage vesicle and is N- methylated in the cytoplasm. The resulting EPI is then pumped back into the vesicle where it remains until released. • GLUCOCORTICOID from the adrenal cortex is essential for EPI synthesis. Glucocorticoid both induces and stabilizes PNMT. Glucocorticoids reach the adrenal medulla from the venous outflow of the surrounding adrenal cortex. • Extra-adrenal chromaffin tissue or tumors of the adrenal (pheochromo-cytomas) are not exposed to high glucocorticoid levels and therefore make only NE. • CA released into the circulation from the adrenal medulla are biologically inactivated by metabolism in well vascularized tissues such as liver and kidney. • Metabolism involves 3-O-methylation on the aromatic ring by catechol-O- methyltransferase (COMT) and oxidative deamination. The amino group is removed by monoamine oxidase (MAO) a mitochondrial enzyme. The resulting aldehyde is converted to an acid by aldehyde dehydrogenase. • The acid, 3-methoxy-4-hydroxymandelic acid (also called vanilmandelic acid or VMA) is excreted in the urine.

EXCRETION OF CATECHOLAMINES (CA) AND METABOLITES

• Over a 24h period, approx. 90% of CA is excreted as the acid, VMA (2000 - 9000 ug/24h), 10% as O-methylated NE or EPI. • Small amounts of NE released from sympathetic nerves supplying blood vessels appear in urine (10-70 ug/24h). • EPI and its O-methylated product, metanephrine come from the adrenal but make up less than 10% of urinary CA or metabolites. • PHEOCHROMOCYTOMAS are tumors of adrenal chromaffin tissue. They may secrete high levels of CA and produce life threatening episodes of hypertension (high BP). Elevated urinary levels of CA and their metabolites are diagnostic. • Treatment is by surgical removal or, when surgery is not possible, with alpha blocking agents (see below).

RECEPTORS

• These are found on the post synaptic (ganglionic) or post junctional (effector) cell membrane and interact with transmitters released from the nerve terminal.

• Receptors function as a coding system. They show a high degree of specificity. Thus, receptor molecules which bind ACh do not bind NE and vice versa. • The response produced (excitation, inhibition) is determined by the properties of the receptor and its transduction mechanism.

CHOLINERGIC RECEPTORS RESPOND TO ACh

Two broad classes of cholinergic receptor exist, NICOTINIC and MUSCARINIC. (FIG 7)

NICOTINIC RECEPTORS

Signaling by ACh in AUTONOMIC GANGLIA is mediated by NICOTINIC RECEPTORS that lie on cell bodies of sympathetic and parasympathetic postganglionic .

• Nicotinic receptors are excited by ACh. • They are also excited and then blocked by . Hence, their name, cholinergic receptors of the nicotinic type or simply nicotinic receptors. • Nicotinic receptors gate a cation selective . When ACh binds to the receptor the channel opens, sodium and potassium ions pass down their electrochemical gradients and the postganglionic is depolarized. • Transmission is FAST. Action potentials in the preganglionic nerve always generate action potentials postganglionically. • The ganglionic nicotinic receptors are not identical to those at the endplate of the skeletal NMJ. They show differences in sensitivity to blocking (antagonists) and slightly different subunit structure.

MUSCARINIC RECEPTORS

Signaling by ACh at EFFECTOR CELLS is mediated by MUSCARINIC RECEPTORS. These receptores are named after the alkaloid that mimics the action of ACh.

• Muscarinic receptors are G-protein coupled. Numerous receptors subtypes have been cloned. • ACh produces excitation of smooth muscle and glands and inhibition of the heart (slowing or ). • The inhibitory receptor in the heart is coupled via a to a that opens in the presence of Ach and slows the rate of of the cardiac pacemaker, the sino-atrial (SA) node. • Other inhibitory muscarinic receptors are negatively coupled to adenylate cyclase via Gi, and decrease cyclic AMP production. • The excitatory muscarinic receptors found on smooth muscle and glands stimulate the production of inositol-1,4,5-trisphosphate (IP3) in response to ACh. They are coupled to phospholipase C over Gq. The IP3 releases calcium from internal stores in muscle or glandular tissue, causing contraction or secretion.

A summary of selected effects of activation of the parasympathetic nervous system is given in Table 1.

Figure 7. ANS RECEPTORS

PHARMACOLOGY OF MUSCARINIC RECEPTORS EFFECTS OF MUSCARINE () AND (ANTAGONIST)

Targets of parasympathetic activity are illustrated with muscarine poisoning. Muscarine is not metabolized and hence produces a marked and prolonged stimulation of muscarinic receptors:

• stimulation of secretory activity of all glands→ Salivation, Sweating, tearing (Lacrimation), nasal and bronchial secretions; • contraction of bladder → Urination; • activation of smooth muscle possessing muscarinic receptors → increase in GI motility → Diarrhea and vomiting (Emesis) • slowing of the heart (bradycardia) • constriction of bronchi → wheezing; • pinpoint pupil () and

Muscarinic receptors are blocked by the muscarinic antagonist, atropine, that was originally obtained from the deadly nightshade, . Atropine reverses the effects of muscarine poisoning.

ACTIONS OF ATROPINE

When given alone, atropine blocks the effects of any ongoing parasympathetic activity. Readily detected effects include:

• inhibition of glandular secretions → dry mouth, dry eyes, dry nasal passages, dry skin • due to the loss (or reduction) of ongoing vagal tone • loss of the pupillary light reflex (pupil is dilated = ) • loss of the ability to focus the lens for near vision ()

ADRENERGIC RECEPTORS

ADRENERGIC RECEPTORS RESPOND TO NE AND EPI

These receptors can be divided into two major classes, alpha and beta, that in turn are further subdivided. All these receptors are G-protein coupled.

ALPHA1 RECEPTORS

• Alpha1 receptors are found on smooth muscle and glands and produce excitation.

• NE and EPI are about equally effective at alpha1 receptors (EPI is actually a bit more potent than NE).

• Neuronally released NE is the physiological agonist for alpha1 receptors.

Alpha1 receptors require high concentrations of catecholamines to be excited. Under physiological conditions, only NE released from sympathetic nerve terminals is present in high enough concentrations to excite alpha1 receptors. Even under stressful conditions, the EPI released from the adrenal does not reach high

enough levels in the blood to excite significant numbers of alpha1 receptors.

• Signal transduction: The alpha1 receptor activation by NE involves IP3 2+ production, IP3-mediated Ca release from the sarcoplasmic reticulum with

smooth muscle contraction or glandular secretion. Some alpha1, receptors may + also couple to a Ca2 permeable ligand-gated cation channel. ALPHA2 RECEPTORS

• Are inhibitory receptors found on nerve terminals (presynaptic). • When present on sympathetic postganglionic nerve terminals, they are called (see FIG 4). Activated when NE is released in large amounts (under high frequency stimulation), they inhibit further NE release from the same terminals (feedback inhibition). activation conserves transmitter under conditions of high utilization.

• Adrenal medullary chromaffin cells do not possess alpha2 receptors. Thus, secretion of EPI is not restrained by feedback inhibition. Chromaffin cells can become depleted of EPI when release is prolonged, for example in response to profound, long lasting stress.

ALPHA2 HETERORECEPTORS

• Alpha2 receptors present on nerve terminals that do not secrete NE (nonadrenergic terminals) are called hetero-receptors.

• Alpha2 hetero-receptors are present on the terminals of postganglionic parasympathetic nerves (very important in the gastrointestinal tract). • When activated by NE released from sympathetic nerves these alpha2 hetero- receptors inhibit evoked release of Ach. In this way, the sympathetic exerts an inhibitory effect indirectly, by reducing the output of excitatory transmitter. This is the principal way in which the sympathetic inhibits activity of the gastrointestinal tract.

• Signal transduction: Activation of alpha2 receptors reduces the magnitude of the inward calcium current that passes into the nerve terminal through voltage sensitive calcium channels that are opened by invading action potentials. As a result, the release of transmitter is reduced.

BETA RECEPTORS

• Beta receptors exist as excitatory beta1 and inhibitory beta2 receptors. Beta receptors are much more sensitive to CA than alpha receptors.

• The beta1 produces excitation in the heart. • EPI and NE are equally effective at beta1 receptors and work at very much lower concentrations than at alpha receptors.

• The beta2 adrenergic receptor produces relaxation of smooth muscle (inhibition). It is found on tracheal and bronchial smooth muscle, in the GI tract and in the smooth muscle of blood vessels supplying the skeletal muscle bed (where it occurs along with alpha1 receptors).

• The beta2 receptor is preferentially activated by EPI. NE is not at all effective at

activating beta2 receptors. • Signal transduction: All beta receptors are positively coupled to adenylate cyclase, via Gs and thus generate cAMP with subsequent activation of protein kinase A and phosphorylation of one or more proteins. The type of response depends on the target protein phosphorylated. This material will be covered in lectures on smooth muscle and heart muscle later in the course.

PHARMACOLOGY OF ADRENERGIC RECEPTORS

Selective blocking agents (antagonists) are available to block the various classes of adrenergic receptors. Some of these drugs are useful clinically, e.g. Beta1 blockers are used as antiarrythmics. Beta2 selective will dilate the bronchi. They are useful in .

SUMMARY OF SYMPATHO-ADRENAL AND PARASYMPATHETIC EFFECTS BY TYPE OF TARGET TISSUE HEART : Sympathetic (NE) or adrenal (EPI) have excitatory effects, increasing the rate of beating and the force of contraction via activation of

BETA1 receptors.

Parasympathetic has an inhibitory effect, slowing the rate of beating

via action of Ach on MUSCARINIC receptors (M2).

SMOOTH Sympathetic excites smooth muscle via ALPHA1 receptor activation MUSCLE: (blood vessels, piloerector muscles);

Adrenal EPI activates BETA2 receptors and produces relaxation of certain smooth muscle (e.g. airways, GI tract & blood vessels supplying skeletal muscle)

Parasympathetic excites most of the smooth muscle it innervates and responses are mediated by MUSCARINIC receptors (smooth muscle of gastrointestinal tract)

GLANDS: Parasympathetic always stimulates glandular secretions, via MUSCARINIC receptors.

Sympathetic stimulates sweating via MUSCARINIC ACTION of ACh on generalized sweat glands and via alpha1 effects of NE on sweat glands of palms of hands.

Review of Sympatho-Adrenal Actions on Organ Systems (see TABLE 1)

TABLE 1. AUTONOMIC EFFECTS ON VARIOUS ORGANS OF THE BODY Receptor Parasympathetic Organ Sympathetic Stimulation Type * Stimulation Eye: Dilates (mydriasis) (radial Narrows (miosis) Pupil m. contracts) (sphincter contracts) Contracts for near Ciliary muscle Relaxes for far vision vision Tear glands: Secretion

Heart: Increased rate Slowed rate

Muscle Increased force Decreased force of atrial of contraction contraction Lung: Airways Relaxation Contraction Glands Increased secretion Systemic blood Abdominal Constriction None vessels: viscera Constriction Skeletal muscle None Dilation + Skin and Constriction None mucosa Gastrointestinal Motility and # tract: Decreased Increased peristalsis and tone tone Sphincters Contracted Relaxed Secretions Inhibited # Stimulated Gallbladder and Relaxation Contraction bile ducts:

Urinary Bladder: Contraction Inhibited Excited

Skin: Piloerector Contraction None muscles palms Secretion None Sweat cholinergic glands generalized Secretion muscarinic None

* Receptor type indicated where definitely known

+ Respond to circulating epinephrine released from adrenal. With the normally low circulating concentrations that occur in response to stressors, you see vasodilatation because receptors are activated preferentially; with high epinephrine concentrations, seen only under pathological conditions, receptors are also activated and vasoconstriction predominates.

# Sympathetic inhibition of gastrointestinal function takes place primarily as a result of inhibition of release of Ach from parasympathetic postganglionic neurons and possibly other excitatory transmitters from peptidergic motor neurons. This action is mediated by

NE released from sympathetic nerve terminals and acting at presynaptic alpha2 heteroreceptors. Inhibition of Ach release from preganglionic parasympathetic neurons may also contribute.

The sympathetic innervation to the GI tract is continuously active, with low level basal discharge (or tone), which reduces the effectiveness of basal excitatory parasympathetic activity. Basal levels of motility and secretory activity reflect the interplay between the tonic parasympathetic and sympathetic inputs.

The remaining effects listed below are important components of the stress response: Alpha and beta effects are involved but are not well characterized in humans.

Sympathetic Parasympathetic Organ Stimulation Stimulation Coagulation Increased None Blood: Glucose Increased None Basal metabolism Increased up to 150% None Liver Glucose released None Adrenal cortical secretion Increased None

Mental activity Increased alertness None Increased glycogenolysis Increased strength of Skeletal Muscle None contraction

Fat Increased lipolysis None

MUSCLES OF THE IRIS DILATOR OR RADIAL SPHINCTER

SYMPATHETIC PARASYMPATHETIC INNERVATION INNERVATION

Figure 8 Stimulation of sympathetic nerves causes Parasympathetic fibers are tonically active. They contraction of the radial muscle and widening of regulate pupil diameter in response to light falling the pupil (MYDRIASIS). Drugs which mimic the on the retina, by contracting the sphincter muscle effect of NE (sympathomimetics) produce the (pupilary light reflex). Stimulation of the same parasympathetic nerves reduces the pupil to a pin effect when instilled into the eye. point (MIOSIS). A similar effect is obtained with drugs that mimic the action of ACh at muscarinic This response is seen in severe stress (fight or receptors or prolong the effects of ACh at the flight response). neuroeffector junction.

Dilation of the pupil results when muscarinic receptors are blocked by ATROPINE

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