Acetylcholine

roles of acetylcholine

movement, learning, memory, cognition, homeostasis, affect, and sleep

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 metabolism

acetylcholinesterase (AChE) degrades ACh into acetate + choline

AChE (acetylcholinesterase)

enzyme found in synapses and neuromuscular junctions that breaks down ACh into acetate + choline

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)

What determines nicotinic vs muscarinic tone?

-affinity of ACh for the different receptor subtypes

-amount of each type of receptor on the membrane

-regulation of the different receptors (desensitization)

muscular nAChRs

pentameric transmembrane LGICs composed of 4 subunits (α2βγδ) that form an ion channel permeable to cations (Na, Ca, and K)

Why does nicotine produce such a wide range of effects?

-nACh receptors are widely distributed in a variety of tissues

-there are a variety of nAChR subtypes or different signaling pathways that mediate different effects

-the active form of nAChR produce different effects than the desensitized form (receptor regulation)

heteromeric neruonal nAChRs

-mostly (α4)2(β2)3 nAChR in brain; high affinity for nicotine

-mostly (α3)2(β4)3 nAChR in ganglia; mediates most of peripheral side effects

both can be desensitized by low doses of agonist without opening

homomeric neuronal nAChRs

(α7)5 nAChR in brain and ganglia that are responsible for cognitive enhancing effects; activated by lower levels of nicotine and desensitized more rapidly by higher doses that transiently activate receptors

Why does chronic nicotine upregulate nAChRs?

-nAChR desensitization causes decreased intracellular signaling and the cell upregulates nAChR in order to try and maintain the signal

-chronic nicotine may reduce nAChR degradation

duration or frequency

LGIC positive allosteric modulators increase the _____ or _____ of channel opening

nicotine

plant alkaloid that is an agonist at nAChRs and has many effects due to varied receptor expression, different receptor subtypes, and different effects when it activates receptors vs when the receptors desensitize

beta2 nAChR subunit

KO of this nAChR subunit produces decreased cellular depolarization relative to WT, also decreases nicotine self-administration, CPP, and withdrawal as well as basal DA levels in response to nicotine

alpha5 nAChR subunit gene

non-synonymous SNP in this gene is highly associated with nicotine dependence and is preserved across species; KO results in increased nicotine SA because the subunit mediates the aversive effects

smoking cessation treatments

-nicotine replacement therapy (full nAChR agonists)

-nAChR antagonists (ex: bupropion)

-partial nAChR agonists (ex: varenicline)

^order of efficacy