Autonomic Pharmacology II Flashcards
Synthesis and Release of Acetylcholine in the Prejunctional Cell
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.
Response to Acetylcholine in the Postjunctional Cell
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
Presynaptic nicotinic receptors
enhance Ca2+ entry into the presynaptic neuron, thereby increasing vesicle fusion and release of ACh
Presynaptic M2 and M4 muscarinic receptors
Inhibit Ca2+ entry into the presynaptic neuron, thereby decreasing vesicle fusion and release of ACh.
Postsynaptic nicotonic receptors
Excitatory
Postsynaptic M1, M3, and M5 muscarinic receptors
Excitatory
Postsynaptic M2 and M4 muscarinic receptors
Inhibitory
NM Receptors
Isoform of nicotinic receptor on the neuromuscular endplate
NN Receptors
Isoform of nicotinic receptor on autonomic ganglia
M1, M3, and M5 are coupled to. . .
Gαq, which leads to stimulation of phospholipase C and thus calcium release.
M2 and M4 are coupled to. . .
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 Gαi, can directly bind and stimulate the function of potassium channels. This is important to decrease heart excitability and slow conduction.
M2 and M4 interaction with β receptors
The adenylate cyclase inhibition stimulated by M2/M4/Gαi signaling interferes with the β receptor/Gαs-mediated adenylate cyclase activation.
There are no ____ in smooth muscle
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.
Myosin isoform found in smooth muscle
Myosin II
Protein Kinase A in smooth muscle
GPCRs that couple to ___ tend to promote smooth muscle contraction, whereas those that couple to ___ tend to promote smooth muscle relaxation.
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.
Smooth muscle regulation diagram
The diameter of the pupil is controlled by antagonistic effects of the sympathetic and parasympathetic nervous system on ____ sets of muscles.
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
Innervation of nasal, lacrimal, salivary, and most gastrointestinal glands
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.
Innervation of the GI tract by sympathetic and parasympathetic nerves
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).
Innervation of the skin by sympathetic and parasympathetic nerves
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)
Innervation of the heart by sympathetic and parasympathetic nerves
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.
Cardiac output
Heart rate (bpm) x stroke volume (mL)
At rest, heart rate is controlled mostly by. . .
The vagus nerve (parasympathetics), by tuning the sinoatrial node’s resting potential via potassium channels.
Innervation of the respiratory tract by smpathetic and parasympathetic nerves
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.
____ are dominant in maintaining airway smooth muscle tone.
Parasympathetic neurons are dominant in maintaining airway smooth muscle tone.
Therefore, anticholinergic agents can cause bronchorelaxation.
Treatment of chronic obstruc5ve pulmonary disease
anticholinergic drug
Treatment of acute asthma attack
Epinephrine or albuterol (β2 selective agonist that may be taken via inhaler)
Innervation of the bladder by smpathetic and parasympathetic nerves
Parasympathetic: M2 and M3 trigger bladder wall contraction.
Sympathetic: β2 and β3 trigger bladder wall relaxation.
____ or ____ may be useful for patients who have overactive bladders.
Antimuscarinics or sympathetic agonists may be useful for patients who have overactive bladders.
Innervation of systemic vasculatory smooth muscle by smpathetic and parasympathetic nerves
Parasympathetic: No effect!!!
Sympathetic: Effects depend on the receptor.
Bloodflow to ___ and ___ is preserved by the activity of ___ in the context of widespread vasoconstriction via α adrenergic receptors.
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.
Affects on metabolic regulation by smpathetic and parasympathetic nerves
Parasympathetic: Minimal effects.
Sympathetic:
- Liver: Increased glycogenolysis and gluconeogenesis via α1 and β2
- Adipose: Increased lipolysis via β3
- Skeletal muscle: Increased glycogenolysis via β2
The Adrenal Medullae
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.
Summary of adrenergic receptor intracellular signaling
Sympathetic and parasympathetic tone table
Quick rule of thumb for remembering the alpha and M interactions
The alphas follow the same rule as the Ms:
Even couples to Gi
Odd couples to Gq
The only autonomic receptor family that promotes relaxation is. . .
The beta receptors, via Gs
Activation of M2 receptors in the cells of the sinoatrial node of the heart may slow the heart rate by
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 VK)
____ can also act as antagonists of the M3 receptor
Antihistamines can also act as antagonists of the M3 receptor
The addition of an ____ to a system with a high degree of tone would show a ____ effect
The addition of an agonist to a system with a high degree of tone would show a small effect
