Cholinergic synapses

Question 1

Synthesis and breakdown of acetylcholine 1

Answer 1

• Acetylecholine (Ach) is synthesized starting w/ phosphatidyl-ethanolamine being methylated by SAM to make phosphatidyl-choline
• The choline is cleaved off and reacted w/ acetyl-CoA by choline acetyltransferase (CAT)
• Choline is the rate-limiting component
• CAT is a marker for cholinergic neurons
• Ach is broken down into choline and acetate by acetylcholinesterase (cholinesterase)
• Choline is transported into pre-neurons by transport proteins or thru membrane-bound lipids

Question 2

Synthesis and breakdown of acetylcholine 2

Answer 2

• Hemicholinium is an inhibitor of the choline uptake system and can deplete neurons of stored Ach
• Physostigimine, sarin, selenophosphates, DIFP, and others all inhibit cholinesterase
• This increases the t1/2 of Ach in synapse
• Can potentially be used to treat myasthenia gravis and AD

Question 3

Ach receptors: nicotinic

Answer 3

• Nicotinic receptor: chemically-gate Na/K channels (ionotropic) that are fast acting, shorter lasting
• Phosphorylation of cytoplasmic domains involved in desensitization
• Excitatory receptors prominent on muscle fibers
• Nicotine is agonist and curare is antagonist
• Composed of 2 alpha, and one beta, gamma, and delta subunits
• Usually pentameric
• CNS nAchR usually A4B2, chronic exposure to nicotine up regulates the A4B2 receptor
• This results in increased Ach-evoked currents and less capacity to desensitization

Question 4

Genetics in nicotine addiction

Answer 4

• There are genetic and environmental factors that predispose one to being addicted to nicotine
• SNPs of A4 subunit, B1, some haplotypes of A5 and A3 all affect nicotine addiction
• Some SNPs in CAT have influences in quitting

Question 5

Myasthenia gravis

Answer 5

• Nicotinic receptor becomes target for autoimmune attack, leading to muscle degeneration
• The target is the A subunit

Question 6

Muscarinic receptors

Answer 6

• Slower acting, longer lasting changes from these receptors
• Are GPCRs and thus use 2nd messengers to either excite or inhibit postsynaptic cell
• Muscarine is agonist, atropine is antagonist
• Muscarinic receptors can inhibit AC, activate PLC, activate K channels
• 5 subtypes and are widely distributed

Question 7

Pharmacological manipulation of cholinergic synapses

Answer 7

• 7 ways: Ach synthesis
• Ach transport into vesicles
• release from presynaptic neuron
• postsynaptic receptor modulation
• presynaptic muscarinic receptor modulation (regulates feedback mechanism)
• cholinesterase inhibition
• choline uptake inhibition

Question 8

Botulism toxin

Answer 8

• Active at NMJs (CNS not involved), is transported into motor neuron terminal, parasym nerve terminal, and peripheral ganglia
• Acts as a Zn-endopeptidase in NMJ motor neurons and destroys the neuro-exocytosis apparatus, thus preventing the release of Ach into the synapse (same mech as tetanus)
• This results in paralysis

Question 9

Tetanus toxin

Answer 9

• Enters peripheral nerve terminals and is transported to the cell body in the spinal cord or brain stem by retrograde transport
• Toxin migrates across the synapse to the presynaptic terminals where it blocks the release of inhibitory NTs GABA or gly from the inhibitory neuron that is synapsing on the motor neuron
• Does this by acting as a Zn-metalloproteinase and preventing the vesicle release (same mech as botulism)
• This leads to constitutive disinhibition of the motor neuron, resulting in tetanic contractions

Question 10

Uses of nicotine

Answer 10

• Possible Rx of AD, PD, and ADHD

- Nicotine based drug ABT 418 reduces AD and hyperactivity (HA) symptoms, but have side effects