Autonomic Pharmacology II

Question 1

Synthesis and Release of Acetylcholine in the Prejunctional Cell

Answer 1

Acetylcholine is synthesized in the terminal endings and varicosities of the cholinergic nerve fibers, where it is stored in vesicles in highly concentrated form until it is released. Choline is transported into the presynaptic cholinergic nerve terminal by a high-affinity Na+-choline co-transporter. The cytosolic enzyme choline acetyltransferase catalyzes the formation of acetylcholine (ACh) from acetyl coenzyme A (AcCoA) and choline. Newly synthesized ACh is packaged into vesicles for storage. Transport of ACh into the vesicle is mediated by a H+-ACh antiporter. The ACh-containing vesicles fuse with the plasma membrane when intracellular calcium levels rise in response to a presynaptic action potential, releasing the neurotransmitter into the synaptic cleft. Acetylcholine diffuses in the synaptic cleft and binds to postsynaptic and presynaptic receptors.

Question 2

Response to Acetylcholine in the Postjunctional Cell

Answer 2

Acetylcholine receptors are divided into nicotinic and muscarinic receptors. Nicotinic receptors are ligand-gated ion channels that are permeable to cations, while muscarinic receptors are G protein-coupled receptors that alter cell signaling pathways, including activation of phospholipase C (PLC), inhibition of adenylyl cyclase (AC), and opening of K+ channels. Acetylcholine in the synaptic cleft is degraded by membrane-bound acetylcholinesterase (AChE) into choline and acetate

Question 3

Presynaptic nicotinic receptors

Answer 3

enhance Ca2+ entry into the presynaptic neuron, thereby increasing vesicle fusion and release of ACh

Question 4

Presynaptic M2 and M4 muscarinic receptors

Answer 4

Inhibit Ca2+ entry into the presynaptic neuron, thereby decreasing vesicle fusion and release of ACh.

Question 5

Postsynaptic nicotonic receptors

Answer 5

Excitatory

Question 6

Postsynaptic M1, M3, and M5 muscarinic receptors

Answer 6

Excitatory

Question 7

Postsynaptic M2 and M4 muscarinic receptors

Answer 7

Inhibitory

Question 8

N_M Receptors

Answer 8

Isoform of nicotinic receptor on the neuromuscular endplate

Question 9

N_N Receptors

Answer 9

Isoform of nicotinic receptor on autonomic ganglia

Question 10

M1, M3, and M5 are coupled to. . .

Answer 10

Gα_q, which leads to stimulation of phospholipase C and thus calcium release.

Question 11

M2 and M4 are coupled to. . .

Answer 11

Gα_{<strong>i</strong>}, which leads to a reduction in cAMP by inhibiting adenylate cyclase.

The β,γ subunits of the G protein, when released from Gα_i, can directly bind and stimulate the function of potassium channels. This is important to decrease heart excitability and slow conduction.

Question 12

M2 and M4 interaction with β receptors

Answer 12

The adenylate cyclase inhibition stimulated by M2/M4/Gα_i signaling interferes with the β receptor/Gα_s-mediated adenylate cyclase activation.

Question 13

There are no ____ in smooth muscle

Answer 13

There are no sarcomeres or tropomyosin in smooth muscle

Instead, smaller contractile units that contain actin and myosin are tethered between elements called dense bodies.

Without tropomyosin, the myosin motor of smooth muscle is always active, although it is a different form of myosin than in skeletal muscle.

Question 14

Myosin isoform found in smooth muscle

Answer 14

Myosin II

Question 15

Protein Kinase A in smooth muscle

Answer 15

Question 16

GPCRs that couple to ___ tend to promote smooth muscle contraction, whereas those that couple to ___ tend to promote smooth muscle relaxation.

Answer 16

GPCRs that couple to Gq (and induce calcium flux via IP₃ and DAG) tend to promote smooth muscle contraction, whereas those that couple to Gs (and induce adenylate cyclase -> PKA activation) tend to promote smooth muscle relaxation.

Question 17

Smooth muscle regulation diagram

Answer 17

Question 18

The diameter of the pupil is controlled by antagonistic effects of the sympathetic and parasympathetic nervous system on ____ sets of muscles.

Answer 18

The diameter of the pupil is controlled by antagonistic effects of the sympathetic and parasympathetic nervous system on separate sets of muscles.

α₁-mediated contraction of the radial muscles causes dilation, while M3-mediated contraction of the circular muscles causes constriction.

Note that this works since both α₁ and M3 utilize the Gq -> PLC -> IP₃/DAG -> Ca²⁺ pathway

Question 19

Innervation of nasal, lacrimal, salivary, and most gastrointestinal glands

Answer 19

Parasympathetic: M3-mediated stimulation of fluid production and myoepithelial contraction

Sympathetic: α₁ promotes some fluid secretion, β₁ promotes protein secretion

There is no antagonism in autonomic signaling in glands.

Question 20

Innervation of the GI tract by sympathetic and parasympathetic nerves

Answer 20

Both the parasympathetic and sympathetic nervous system can affect gastrointestinal activity mainly by increasing or decreasing specific actions in the intestinal enteric nervous system.

Parasympathetic: Promotes peristalsis and sphincter relaxation. M3 signal via calcium to induce peristalsis, M2 signal via adenylate cyclase inhibition to antagonize sympathetic effects on peristalsis. Sphincter relaxation is mediated indirectly via ACh-dependent nitrous oxide production.

Sympathetic: Inhibits peristalsis (β₂) and constricts sphincters (α₁).

Question 21

Innervation of the skin by sympathetic and parasympathetic nerves

Answer 21

Parasympathetic: Does not innervate the skin or nerves!!!

Sympathetic: Induces contraction of blood vessels via α₁. Induces stimulation of sweat glands via M2 and M3 (the only terminal cholinergic action of the symapthetic nervous system)

Question 22

Innervation of the heart by sympathetic and parasympathetic nerves

Answer 22

Sympathetic: Increased heart rate and contractility via β₁

Parasympathetic: Decreased heart rate and contractility via M2. Heart rate affects are accomplished via the βγ subunits of Gi, which open potassium channels and hyperpolarize cardiac cells. It also antagonizes the effects of β₁ by inhibiting adenylate cyclase.

Question 23

Cardiac output

Answer 23

Heart rate (bpm) x stroke volume (mL)

Question 24

At rest, heart rate is controlled mostly by. . .

Answer 24

The vagus nerve (parasympathetics), by tuning the sinoatrial node’s resting potential via potassium channels.

Question 25

Innervation of the respiratory tract by smpathetic and parasympathetic nerves

Answer 25

Sympathetic: There is little adrenergic innervation of bronchial smooth muscle, but **airway smooth muscle expresses β₂** which responds to **circulating epinephrine**. **β₂ **-\> cAMP -\> PKA -\> **MLCK inhibition and MLCP activation** Parasympathetic: **Vagus nerve** innervates the lungs. **Airway smooth muscle** cells express **M3 coupled to Gq**. **Calcium** mobilization leads to contraction. These cells also express **M2** which **antagonizes** **β₂** signaling.

Question 26

\_\_\_\_ are dominant in maintaining airway smooth muscle tone.

Answer 26

**Parasympathetic neurons** are dominant in maintaining airway smooth muscle tone. Therefore, **anticholinergic agents can cause bronchorelaxation.**

Question 27

Treatment of chronic obstruc5ve pulmonary disease

Answer 27

anticholinergic drug

Question 28

Treatment of acute asthma attack

Answer 28

Epinephrine or **albuterol** (β₂ selective agonist that may be taken via inhaler)

Question 29

Innervation of the bladder by smpathetic and parasympathetic nerves

Answer 29

Parasympathetic: **M2 and M3** trigger **bladder wall contraction.** Sympathetic: **β₂ and β₃** trigger **bladder wall relaxation**.

Question 30

\_\_\_\_ or ____ may be useful for patients who have overactive bladders.

Answer 30

**Antimuscarinics** or **sympathetic agonists** may be useful for patients who have overactive bladders.

Question 31

Innervation of systemic vasculatory smooth muscle by smpathetic and parasympathetic nerves

Answer 31

Parasympathetic: **No effect!**!! Sympathetic: Effects depend on the receptor.

Question 32

Bloodflow to ___ and ___ is preserved by the activity of ___ in the context of widespread vasoconstriction via α adrenergic receptors.

Answer 32

Bloodflow to **the coronary arteries** and **skeletal muscle** is preserved by the activity of **β₁ adrenergic receptors** in the context of widespread vasoconstriction via α adrenergic receptors.

Question 33

Affects on metabolic regulation by smpathetic and parasympathetic nerves

Answer 33

Parasympathetic: **Minimal effects**. Sympathetic: * **Liver**: Increased **glycogenolysis and gluconeogenesis** via **α₁ and β₂** * **Adipose**: Increased **lipolysis via β₃** * **Skeletal muscle**: Increased **glycogenolysis via β₂**

Question 34

The Adrenal Medullae

Answer 34

Sympathetic: Release of 80% epinephrine 20% norepinephrine into the bloodstream. The circulating epinephrine and norepinephrine have almost the **same effects** on the different organs as the effects caused by **direct sympathetic stimulation**, except that the effects **last 5 to 10 times as long** because both of these hormones are **removed from the blood slowly over a period of 2 to 4 minutes.**

Question 35

Summary of adrenergic receptor intracellular signaling

Answer 35

Question 36

Sympathetic and parasympathetic tone table

Answer 36

Question 37

Quick rule of thumb for remembering the alpha and M interactions

Answer 37

The alphas follow the same rule as the Ms: Even couples to Gi Odd couples to Gq

Question 38

The only autonomic receptor family that promotes relaxation is. . .

Answer 38

The beta receptors, via Gs

Question 39

Activation of M2 receptors in the cells of the sinoatrial node of the heart may slow the heart rate by

Answer 39

**Increasing the amount of beta/gamma subunits of G proteins** available to interact with downstream target proteins, specifically by **activating potassium channels** and making the **polarization of the membrane more negative (closer to V_K)**

Question 40

\_\_\_\_ can also act as antagonists of the M3 receptor

Answer 40

**Antihistamines** can also act as antagonists of the M3 receptor

Question 41

The addition of an ____ to a system with a high degree of tone would show a ____ effect

Answer 41

The addition of an **agonist** to a system with a high degree of tone would show a **small** effect