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

 

(Previous version: classify the mechanisms of neurotransmitters)

 

List:

·       Intro

·       Classification

·       Adrenergic

·       Cholinergic

·       NANC

 

Intro:

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)

 

Classification:

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

 

Cholinergic transmission: e.g. ACh at nAChR

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

 

Adrenergic transmission: e.g. adrenaline at β1

Features

·  Metabotropic – via second messenger

·  Multi-step amplification (GPCR to Gs, Gs 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

 

Non-adrenergic non-cholinergic (NANC):

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