Acetylcholine

Question 1

Ach Synthesis

Answer 1

1 Step with 2 precursors:

choline + acetyl CoA –(ChAT)–> Ach + Coenzyme A

• choline comes from fat in our diet
• acetyl CoA comes from metabolism of sugars and fats
• Coenzyme A is a byproduct!
• -> ChAT is an enzyme found only in Ach cells.
• Rate of synthesis depends on (1) availability of precursors and (2) rate of cell firing*

After synthesized packaged into vesicles by vesicular Ach transporter – VAchT
—-> drug: vesamicol blocks VAchT and increase Ach concentration in the cytoplasm (resperpine for Ach)

Question 2

Ach Breakdown

Answer 2

Broken down by acetylcholinesterase - AchE:
Ach –(AchE)–> acetic acid + choline
-AchE present in different places on neuron/synapse:
–presynaptic
–on membrane of post synaptic cell
–neuromuscular junctions (different for precise transmission)
—-drug: Sarin = irreversible AchE blocker (CNS and PNS) - ‘nerve gas’
—-drug: physostigmine - blocks AchE in the CNS and prevents Ach inactivation.

Once Ach broken down in cleft - choline taken back up by cholinergic transporter/ high affinity choline uptake (HACU)
—-drug: HC-3 blocks cholinergic transporter and decreases Ach synthesis (not like SSRI function) * we can’t live without cholinergic transporter –> recycled choline is vital to Ach transmission!!

Question 3

Organization and Function of Ach System: PNS

Answer 3

(Key role in both CNS and PNS Functioning)

PNS:
-preganglionic autonomic neurons use Ach
–> parasymp. system continues to use Ach as activating NT at organs.
Function: parasymp. ns activation, signaling for parasymp and symp. ns.

• motor neurons/ neuromuscular junction
  function: neuromuscular activation

Question 4

Organization and Function of Ach System: CNS

Answer 4

(Key role in both CNS and PNS Functioning)

CNS:
Several important clusters of Ach neurons in the brain:

Striatum:
-counters DA input for motor movement and INHIBITS movement – glance between DA and Ach plays a big role in parkinson’s
Function: inhibition of basal ganglia in the forebrain

Basal Forebrain Cholinergic System (BFCS):
-origin of Ach projections to the cortex, hippo, and amyg.
-important for cognition - learning and attention
Function: learning, memory, attention

Dorsolateral Pons/ Pontomesencephalon:
-Laterodorsal tegmental nuclei: LDTg
—LDTg projects to VTA
-Pedunculopontine tegmental nuclei: PPTg
—PPTg projects to the SN
–> regions important for REM sleep onset and waking (via thalamic relay neuron up regulation), also sensory processing and arousal.
Function: activation of DA neurons of the VTA (reward), activation of the forebrain (RAS), activation of REM sleep.

Question 5

Ach Receptors

Answer 5

2 Subtypes:

1) Nicotinic
2) Muscarinic

Question 6

Nicotinic Receptors

Answer 6

Ionotropic

• selectively respond to nicotine as an agonist
• more dense on muscle cells, ganglionic neurons, and some times of brain neurons
• when activated opens Na+ and Ca2+ channels to allow ion entry to cell –> EPSP/ muscle contraction.
• 5 Subunits: muscle and neuronal differ in composition

—–> Muscle Nicotinic: normally 2 alpha, 1 beta, 1 gamma, and either 1 delta or 1 epsilon –> Contains 2 Ach Binding Sites (on the alpha subunits) and BOTH must be activated to open channels –> COINCIDENCE BINDING

—–> Neuronal Nicotinic: either 2 alpha and 2 beta or 5 alpha.

-presynaptic nicotinic: can stimulate increased release of NT into the synapse

-Can be DESENSITIZED when continuously exposed to agonist (then channel remains closed regardless of agonist activation) – after awhile will eventually resensitizes passively…
…still.. some receptors don’t desensitize and remain active and continue to depolarize - if prolonged, can cause a DEPOLARIZATION BLOCK which means the membrane potential is lost and no APs can be propagated until the agonist is removed and the potential repolarizes.
—–drug: succinylcholine: resists AchE breakdown and creates a depol. block - acts as a muscle relaxant.

Question 7

Muscarinic Receptors

Answer 7

Metabotropic
5 types: M1-M5
-M1,3,5 = SLOW EXCITATION via 2nd messanger systems: phosphoinositide to activate PKC
-M2,4 = INHIBITION via k+ channel opening, and inhibiting adenylyl cyclase.

Found in PNS and CNS:

• PNS: parasympathetic nervous system: heart and smooth muscle of internal organs:
• -activation slows heart (M2)
• -activation contracts smooth muscle (M3)
• -> high density also in beta cells of pancreas (M3)

-CNS: widely distributed: telencephelon: neocortex and hippo (cognitive functions) and striatum (motor functions), and midbrain mesencephelon: can stimulate DA release.

—> M5’s may play a role in morphine dependence:
LDTg excitatory projection to the VTA produces dopamine release on the NA. This projection to the VTA is mediated in part by M5 receptors. M5 knockout mice show decreased performance on morphine and cocaine place preference tests. Therefore M5 may be involved in the rewarding and dependence producing effects of drugs.