Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA +...

14
holine (ACH) oA + Cholin A Choline-acetyl-transferase (C oA + Cholin A Acetylcholine-esterase

Transcript of Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA +...

Page 1: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Acetylcholine (ACH)

Acetyl-CoA + Cholin ACH +CoA

Choline-acetyl-transferase (CAT)

Acetyl-CoA + Cholin ACH +CoA

Acetylcholine-esterase

Page 2: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

TrimethylAmino-Ethanol

Page 3: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

ACH synapse

Presynpase acetate + choline ACH

transporter----------------------------------------------choline------------

Synaptic cleft ACH-esterase---------------------------------------------------------------------------------

Postsynapse excitatory R: Ionotropic: Nicotin R metab.: Muscarinic R inhibitory R: metab.: Muscarinic R

Page 4: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.
Page 5: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Postsynaptic ACH receptors

Nicotinic receptorIonotropic, cation (Na+) channel

Pentameric: 5 transmembrane proteins=subunits 2 α, 1β, 1γ, 1δ

in the brain: hetero-pentameric: α2-8, β2-4 homo-pentameric: α7, 8

Page 6: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.
Page 7: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Muscarinic receptors M1 – M5

metabotropicexcitatory: slow long lasting depolarisation due to closure of the K+ channel M1, M3, M5

inhibitory: slow long lasting hyperpolarisation due to opening of the K+ channel M2, M4

ACH auto-receptorsN receptor: positive feed-back, fast onset fast desensitizationM receptor negative feed back, slow onset slow desensitization

Page 8: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Acetylcholine AgonistsDirect Parasympathomimetics

Rezeptor Agonist

N Nicotine

M MuskarinPilocarpin

M, N CarbacholArecolin

Indirect ACH-AgonistsIndirect Parasympathomimetics

mode of action:ACH-Esterase inhibition

reversible inhibitors:PhysostigmineEserineNeostigmine

irreversible inhibitors:ParathioneNitrostigmineE 605Sarin, Tabun, Soman

ACH-AntagonistsDirect Parasympatholytics

M Belladonna AlkaloidsScopolamineAtropinePirenzepine

N CurareGallamin, FlaxedilSuxamethoniumMecamylamine, Hexamethonium

Indirect ACH-AntagonistsIndirect Parasympatholytics

HemicholinumBotulinus Toxin

Neuropharmacology Uni-Tuebingen

Page 9: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Cotransmitters of ACH

Cortex of the rat: Vasoactive intestinal peptide (VIP)N. Cochlearis: EncephalinNBM/ Septum: Substance PATP

Page 10: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.
Page 11: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Specific toxins for ACH neurons

AF 64: CAT inactivation inhibits the transporter (by alcylation) 192 IgG-Saporin: Immunotoxin antibody against p75NGF (=low affinity NGF receptor which is localized upon ACH neurons)

Page 12: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Anatomy of the ACH System

Periphery: Motor end plate Vegetaive NS: Sympathicus preganglionic: ACH - N receptor postganglionic: Noradrenalin Parasympath. preganglionic: ACH – N receptor postanglionic: ACH – M receptor

Brain: 5 –10 % are ACH ergic

Nucleus basalis whole cortex

Septum hippocampus

PPTg VTA (mesencephalon)

Page 13: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Figure: Central cholinergic pathways. The six major cholinergic projection groups (sectors) are depicted (Ch1-Ch6). Therein, projections from Ch1/Ch2 and Ch4 to hippocampal, limbic and neocortical areas are implicated in learning and memory processes. 

Page 14: Acetylcholine (ACH) Acetyl-CoA + Cholin ACH +CoA Choline-acetyl-transferase (CAT) Acetyl-CoA + Cholin ACH +CoA Acetylcholine-esterase.

Physiology/Pathophysiology of ACH

Septum – hippocampus: learning, M-receptor mediated

hippocampal theta rhythm transiently during orienting behaviour M-receptor mediated

NBM - cortex learning N+M receptor mediated attention

PPTg – VTA brain reward