2012A12 Describe the main mechanisms by which chemical neurotransmitters exert their effects,
using examples from the autonomic nervous system.

Definition

·   Small molecule released by a cell to affect an immediately adjacent cell

Production

·   Synthesised from amino acids, metabolic intermediates

·   Transported into vesicles (e.g. VMAT for noradrenaline (NAd))

Release

·   Cell activation e.g. ↑ICF [Ca²⁺]

·   Released by exocytosis

·   Crosses synaptic cleft

Binding

·   On adjacent cell (e.g. ACh to ganglionic nAChR)

·   On itself (NAd to presynaptic α₂ adrenoceptor)

Removal

·   ± Degradation in synaptic cleft (e.g. AChE)

·   ± Active reuptake by releasing cell (e.g. NAd)

By autonomic division

·   Adrenergic

o  Adrenaline

o  Noradrenaline

·   Cholinergic

o  Acetylcholine

·   Non-adrenergic, non-cholinergic (NANC)

o  eNANC: substance P, NK-A

o  iNANC: NO, VIP

o  Both: NPY

By type of molecule

·   Gas: e.g. nitric oxide (NANC)

·   Amino acid (e.g. glycine)

·   Peptide e.g. NPY (NANC)

·   Monoamine e.g. noradrenaline

By direction of effect

·   Excitatory: e.g. adrenaline β₁

·   Inhibitory: e.g. muscarinic m₁

Features

·   Ionotropic: activates ligand-gated ion channel

·   Immediate effect: milliseconds between exocytosis and effect

·   Short-lived: ceases upon dissociation of ligand from receptor

Mechanism

·   ACh binds α-subunit of nAChR

·   ↑Central ionophore permeability

·   Na⁺ influx = K⁺ efflux > Ca²⁺ influx

·   Depolarisation = mini-end plate potential

·   Spatial + temporal summation -> action potential

Features

·   Metabotropic – via second messenger

·   Multi-step amplification (GPCR to G_s, G_s to AC, AC to cAMP)

·   Self-limitation (α-GTP hydrolyses during interaction with AC)

·   Slower onset (e.g. seconds)

·   Longer duration than ligand-binding (e.g. minutes)

Mechanism

·   Gs: e.g. adrenaline β₁ myocardium

·   α-GTP activates adenylyl cyclase

·   ↑[cAMP]

·   ↑activity PKA-> phosphorylation of…

o  Myosin: ↑rate of cross-bridge cycling

o  L-Ca²⁺ channel: ↑rate of Ca²⁺ influx

o  TNI and phospholamban: ↑rate of relaxation

Excitatory

(eNANC)

e.g. substance P

·   Receptor is NK-1, metabotropic

·   Cell-dependent effects

Inhibitory

(iNANC)

e.g. nitric oxide

·   NO activates guanylyl cyclase

·   ↑[cGMP]

·   ↑activity PKG

·   Phosphorylation and activation of MLCP -> relaxation