M1i: Outline the production, release & fate of cholinergic transmitters and their end products

ACH = the 1° neurotransmitter (NT) of the ANS

ACH

Synthesis

  • In cytoplasm of preganglionic n. & postganglionic (presynaptic) n.

Acetyl CoA + Choline →(enzyme choline acetyle transferase) → ACh

  • Acetyl CoA in abundance from mitochondria (Kreb’s cycle)
  • Choline enters n. endings cytoplasm from ECF by active transport ( = RATE LIMITING STEP OF ACh SYNTHESIS)

Storage & Release

  • Stored in synaptic vesicles
  • Each n. ~300,000 ACh vesicles
  • Arrival AP → depolarisation → Ca2+ influx → release ~100 ACh vesicles
  • Ca2+ in ECF is essential → antagonised by Mg2+

Metabolism

Metabolism
  • ACh effect at receptors < 1ms
  • Rapid hydrolysis by Acetylcholinesterase
  • Choline transported back into nerve ending

ACh NT

  • Entire parasymp. NS (nerves & ganglia)
  • ganglia, adrenal medulla, sweat glands
  • Somatic nerve innerv. to skeletal m.
  • Some CNS nerves

Cholinesterases

2 types

1. Acetylcholinesterase

  • Located at cholinergic synapses
  • Pre-post junctionally
  • Hydrolyses: ACh → choline + Acetyl CoA
Acetylcholinesterase
  • The enzyme has an ANIONIC SITE & ESTERIC SITE
  • Once AChE hydrolyses ACh the enzyme becomes acetylated & choline is released
  • The enzyme is then ready to hydrolyse the next ACh
  • AChE can hydrolyse 300,000 x ACh per minute!
  • 50% choline is recycled to form new ACh

2. Plasma Cholinesterase

  • Less specific
  • Can hydrolyse many esters inc. ACh, procaine, suxamethonium
  • Synthesised in liver → present in plasma

Cholinergic Receptors

  • Classified depending on their reaction to alkaloids

1. Nicotinic Receptors

  • LIGAND-GATED ION CHANNELS
    • Membrane protein with 5 subunits (α1, α2, β, γ, δ)
    • 2 alpha units occupied by ACh → conformational ∆ → ion channel opens → Na+ IN and K+ OUT
  • Location
    • Entire parasymp. NS
    • All autonomic ganglia
    • Adrenal medulla
    • Sweat glands
    • NMJ

2. Muscarinic Receptors

  • G PROTEIN LINKED
  • 5 subtypes:
    • Even No’s = Gi = regulate AC
    • Odd No’s = Gq = regulate phospholipase C

SUBTYPE

2nd MSG

LOCATION

EFFECT

M1

Gq activates phospholipase C

↑ IP3 & DAG

↑ intracell. Ca2+

CNS

Gastric parietal cells

Membrane hyperpolarisation → ↑memory & seizure activity

↑Acid secretion

M2

Gi → inhibits AC

↓CAMP

↓Ca2+

Heart conducting tissue

-ve CHRONO

-ve DROMO

-ve INOTROPY

M3

Gq → activates phospholipase C

↑ IP3 & DAG

↑ intracell. Ca2+

Glands

Smooth muscle

Vessels

↑ smooth muscle contraction

↑ gland secretion

M4 & 5

Gi / Gq

?CNS

?Facilitates dopamine release