PSNS and Cholinergic Signaling

acetylcholine (ACh)

primary neurotransmitter in PSNS, which contains a quaternary amine and an acyl carbon important for binding

ACh synthesis

acetyl-CoA + choline → acetylcholine by choline acetyltransferase (ChAT)

ChAT (choline acetyltransferase)

enzyme that synthesizes ACh from acetyl-CoA and choline

rate-limiting step of ACh synthesis

uptake of choline into nerve terminal by ChT (choline transporter)

ACh packaging

ACh is transported into vesicles by vAChT (vesicular acetylcholine transporter)

ACh metabolism

acetylcholinesterase (AChE) degrades ACh into acetate + choline

AChE (acetylcholinesterase)

enzyme found in synapses and neuromuscular junctions that breaks down ACh into acetate + choline; contains an anionic site that binds to the quaternary amino group and an esteratic site that binds to the acyl carbon of ACh

esteratic site (AChE)

site of AChE containing a catalytic triad of amino acids, including a glutamate residue that anchors ACh to the enzyme and histidine and serine residues that hydrolyze the ACh molecule

BuChE (pseudocholinesterase)

enzyme found in the plasma that can also breakdown ACh

muscarinic receptors (mAChRs)

five GPCRs with 1 subunit and 7 transmembrane domains that bind to ACh; can be either stimulatory or inhibitory

stimulatory (Gq-coupled), inhibitory (Gi-coupled)

M1, M3, and M5 mAChRs are ___ while M2 and M4 mAChRs are ___

M1 receptors

mAChR expressed in the gut; activation increases intesitinal motility and gastric acid secretion

M2 receptors

mAChRs expressed in the heart; activation decreases heart rate, contraactility, and conduction velocity

M3 receptors

mAChRs expressed in various ANS tissues (sweat glands, bronchioles, bladder, iris sphincter muscles, etc.); activation the vasculature produces some vasodilation due to indirect NO release, in bladder relaxes sphincter muscle, in the eye produces miosis, in salivary glands produces salivation, and in sweat glands produces sweating (SNS)

nicotinic receptors (nAChRs)

ligand-gated cation channel composed of 5 subunits containing a pore lined with negatively charged amino acids that, when activated, opens to allow Na+ and Ca2+ to enter the cell and K+ to leave the cell, causing depolarization (excitatory) until the receptor becomes desensitized and closes

nAChR agonist binding site

interface of α subunit with a different type of subunit (beta in ganglionic and CNS receptors or others in muscle receptors)

cholinergics

compounds that directly or indirectly increase activation of nAChRs and mAChRs

direct acting cholinergics

nAChR or mAChR agonists; effects can be separated by ganglionic effects and NMJ effects due to different subtype composition of nAChRs

nAChR agonists/partial agonists

drugs that are ganglionic stimulants and can be used sometimes for smoking cessation

full agonist, partial agonists

nicotine is a _____ at nAChRs, while lobeline and varenicline are _____ at nAChRs

desensitization, toxicity

the half-life of nicotine is much longer than ACh (~2 hours), meaning that _____ occurs for longer than if ACh, which will be metabolized quickly, was bound; _____ is also much more likely

initial effects of nicotine toxicity

includes sweating, chills, abdominal pain, diarrhea, and increased salivation; caused by overstimulation of the autonomic ganglia (ganglionic stimulation) and CNS effects due to nAChR overactivation

late effects of nicotine toxicity

includes heart rate fluctuations, weakness, breathlessness, and decreased blood pressure; caused by ganglionic blockade at the autonomic ganglia and NMJ as a result of receptor desensitization

adverse nicotinic cholinergic toxicity effects

mydriasis, tachycardia, weakness, hyperthermia, and fasciculations (muscle disturbance); can't be treated with antagonists because the receptor is already desensitized, so it must be treated by inducing vomiting and mechanical respiration

mAChR agonists

include choline esters and alkaloids such as muscarine and pilocarpine

adverse muscarinic cholinergic toxicity effects

includes DUMBBELS (diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, and salivation); typically treated with activated charcoal to absorb remaining toxins or sometimes with specific antidotes if the source of toxicity is known

axoaxonic effects

both nAChR and mAChR agonists can produce _____ that modulate various aspects of the CNS

indirect acting cholinergics

drugs that are either reversible or irreversible AChE/BuChE inhibitors; occupy the anionic site and/or esteratic site of the enzyme, which blocks it from metabolizing ACh

reversible AChE inhibitors

drugs that have an amine group and acyl carbon that bind to the anionic and esteratic sites, respectively, of AChE blocking ACh from binding and being metabolized, but will eventually dissociate from the enzyme; can be used to treat myasthenia gravis, glaucoma, and anticholinergic toxicity as well as increase GI motility

quarternary ammonium compounds

reversible AChE inhibitors such as edrophonium and ambenonium

carbamates

reversible AChE inhibitors such as neostigmine, physostigmine, and pyridostigmine

myasthenia gravis

an autoimmune disorder characterized by degradation of neuromuscular junction nAChRs and widening of synaptic junctions; can be diagnosed by administering edrophonium on the eye to determine if eye muscle tone returns; can be treated with neostigmine

irreversible AChE inhibitors

organophosphates, such as nerve gases and pesticides, that form a covalent bond with the esteratic site of of AChE (aging)

2-PAM

drug used to treat irreversible AChE inhibitor toxicity; binds to the anionic site of AChE and then binds directly to the organophosphate to compete it away from the enzyme, regenerating its function

echothiopate

locally acting irreversible AChE inhibitor used to treat glaucoma

α3β4 nAChRs, M2, M1, other receptors

Ganglionic signaling is mediated by several receptors, including _____ that mediate fast EPSPs, _____ receptors that mediate slow IPSPs, _____ receptors that mediate EPSPs, and _____ (peptides, 5-HT, etc.) mediate slow EPSPs

ganglioinic blockers

nAChR antagonists are _____, which unmask the predominant tone of whichever system (SNS or PSNS) is the most active at baseline

oppose PSNS activation

For most organs, including heart, iris and ciliary muscle of eyes, GI tract, bladder, and salivary glands, the PSNS is the predominant system; ganglionic blockage therefore will produce symptoms that _____ (ex: tachycardia, mydriasis, urinary retention)

oppose SNS activation

For some organs, such as bronchioles, veins, and sweat glands, the SNS is the predominant system; ganglionic blockage therefore will produce symptoms that _____ (ex: bronchoconstriction, vasodilation, decreased sweat production)

ganglionic stimulants

drugs that stimulate nicotinic receptors in autonomic ganglia either directly or indirectly; can have duel effects on the ANS including an early, stimulatory phase during activation and a late, inhibitory phase following receptor desensitization

similar, oppose

ganglionic stimulants first produce symptoms that are _____ to activation of the predominant system while the receptor is activated followed by symptoms that _____ the predominant system once the receptor desensitizes

mAChR activation

Organophosphates (indirect ganglionic stimulants) produce effects via _____ that override effects of nAChR desensitization

bradycardia, tachycardia

Because PSNS is the predominant system in the heart, ganglionic stimulation would first cause _____ via M2 receptors, followed by _____ once the receptors are desensitized

miosis, mydriasis

Because PSNS is the predominant system controlling pupil size, ganglionic stimulants would first cause _____ via M3 receptors, followed by _____ once receptors are desensitized

increased tear secretion

Ganglionic blockade produces _____ via M3 activation

diarrhea/increased GI motility, constipation/decreased GI motility

Because PSNS is the predominant system controlling the GI tract, there would first be _____ via M1 activation followed by _____ once receptors are desensitized

increased urination, urinary retention

Because PSNS is the predominant system controlling bladder muscles, ganglionic stimulants would first cause _____ via M3 receptors followed by _____ once receptors are desensitized

increased saliva secretion, decreased saliva/dry mouth

Because PSNS is the predominant system controlling salivation, ganglionic stimulants would first cause _____ via M3 receptors followed by _____ once receptors are desensitized

bronchodilation, bronchoconstriction

Because SNS is the predominant system controlling the bronchioles, ganglionic stimulants would first cause _____ via β2 activation followed by _____ via M3 activation

vasoconstriction, vasodilation

Because SNS is the predominant system controlling the vasculature, ganglionic stimulants would first cause _____ via α1 activation followed by _____ via M3 activation

increased sweating

Because the SNS is the only system controlling sweat glands, ganglionic stimulation would produce _____ via M3 activation

anti-cholinergics (parasympatholytics)

drugs that oppose the actions of nAChRs or mAChR, either directly or indirectly

direct acting anticholinergics

includes mAChR and nAChR antagonists

mAChR antagonists

anti-muscarinics that block mAChRs in PSNS effector junctions as well as sweat gland junctions (ex: atropine or scopolamine), producing tachycardia, vasodilation, relaxation/decreased motility of GI tract and urinary tract, bronchodilation, mydriasis, decreased sweating, and CNS side effects such delirium; can also antagonize nAChR to cause hypotension at high concentrations

cholinesterase inhibitors, α agonists

antimuscarinic toxicity can be treated with quaternary _____ such as neostigmine or physostigmine, or _____ to treat hypotension

belladonna alkaloids

anti-muscarinics including atropine and scopolamine, which have significant CNS effects

atropine

mAChR antagonist that is a belladonna alkaloid; can have initial muscarinic effects while it activates M2 autoreceptors, but as occupancy increases postsynaptic receptor activation increases to produce the anti-muscarinic effects

nAChR antagonists

anti-nicotinics that block nAChRs in the autonomic ganglia, inhibiting receptors in both the SNS and PSNS

plant-based or venom-based alkaloids

alkaloids such as curare or cobratoxins/conatoxins, respectively, that act as nAChR antagonists

synthetic nAChR antagonists

incldues gallamine, rocuronium, and vecuronium; can be used as muscle relaxers

rocuronium and vecuronium

nAChR antagonists with short half-lives used to induce muscle paralysis before surgery

succinylcholine

nAChR antagonist previously used to induce muscle paralysis before surgery; replaced by newer drugs because it can cause cholinergic crisis in people with BuChE deficiencies

indirect acting anti-cholinergics (parasympatholytics)

oppose actions of PSNS via inhibition of choline uptake (ex: hemicholinium) to decrease ACh synthesis, inhibition of vAChT (ex: vesamicol) to prevent packaging of ACh into vesicles, or inhibition of exocytosis of ACh vesicles (ex: botulinum toxin)

hemicholinium

indirect acting anti-cholinergic that inhibits choline uptake into the nerve, decreasing ACh synthesis

vesamicol

indirect acting anti-cholinergic that inhibits vAChT to prevent packaging of ACh into vesicles

botulinum toxin

indirect acting anti-cholinergic that prevents anchoring of ACh vesicles to the plasma membrane, which prevents exocytosis; can be used to treat facial muscle spasms