4 - Neurotransmitters & main functions Flashcards
Acetylcholine
• First neurotransmitter to be discovered in 1912
• Synthesis: Acetyl coA + Choline Acetylcholine (via Choline acetyl
transferase)
• Breakdown (on postsynaptic neuron):
Acetylcholine = Acetate + choline (via acetylcholinesterase)
Acetylcholine receptors
- Acetylcholine binds to receptors on postsynaptic neurons
- 2 main types: nicotinic (neuromuscular junction, brain, autonomic nerves) or muscarinic (smooth muscle, exocrine glands, brain)
agonists and antagonists
• Agonists are drugs that mimic the actions of the neurotransmitter
- Binding to the receptor = activation
• Antagonists are drugs that block the action of the neurotransmitter
- Binding to the receptor = no activation
cholinergic agonists and antagonists
Nicotinic receptors:
- agonist: nicotine (tobacco)
- antagonist: Curare (paralysis + poison)
Muscarinic receptors:
- agonist: muscarine (toadstool)
- antagonist: atropine (deadly nightshade)
Alzheimer’s disease
- First described by Dr. Alois Alzheimer
- Progressive onset of dementia, including problems with memory
- Neuropathological changes include loss of brain weight, enlargement of ventricles, numerous senile plaques andq neurofibrillary tangles(NFTs) in the brain
Cholinergic death in Alzheimer’s
- Acetylcholine is important for memory and attention
* Cholinergic neurons die early in AD
AChE inhibitors for treatment of AD
AChE inhibitors are one of only 2 approved drugs for the treatment of AD
• donepezil (1997)
• rivastigmine (2000)
• galantamine (2001)
Synthesis of catecholamines
Catechol group = phenol ring with -OH groups in 3 & 4 positions
• Synthesised from tyrosine, which is transported into the brain from the blood
• Catabolism involves enzymes monoamine oxidase (MAO) and catechol 0-
methyltransferase (COMT)
Dopamine signalling
- 2 major families of dopamine receptors
- D1-like: D1 & D5
- D2-like: D2, D3, D4
- D1-like are coupled to stimulatory G-proteins
- D2-like are coupled to inhibitory G-proteins
- All signal via adenylate cyclase & second messengers
Parkinson’s disease
• First described in 1817 by James Parkinson • Mean age of onset ~ 60 yrs • Affects 1-2% over 65 yrs Characterised by: • muscle stiffness • slowness of movement • tremor at rest
Pathology of Parkinson’s disease
- Degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta and loss of dopamine in the caudate-putamen
- > 50% depletion of dopamine
Treatment of Parkinson’s
- Motor symptoms of PD are alleviated by treatment with L-dopa which is transported into brain and converted to dopamine
- Administration of a peripherally active Dopa decarboxylase inhibitor prevents premature conversion of L-dopa to dopamine
- Inhibitors of COMPT and MAO-B can also be given to inhibit dopamine degradation
Synthesis & catabolism of serotonin
- Synthesised from tryptophan by tryptophan hydroxylase and 5-hydroxytryptophan (5-HTP) decarboxylase
- Broken down to 5-hydroxyindoleactic acid (5-HIAA) by MAO and aldehyde dehydrogenase
Serotonin signalling
- 5-HT can bind to 14 different receptors which are all G-protein-coupled, except for 5-HT3 which is a ligand-gated ion channel
- Some receptors are excitatory, others inhibitory
- Action terminated mainly by reuptake from the synapse via the 5-HT transporter on the presynaptic neuron
SSRI treatment for depression & anxiety
- Selective serotonin reuptake inhibitors (SSRIs) block the action of SERT = more serotonin at the synapse
- Can help to reduce symptoms of depression, anxiety, OCD, PTSD, etc.
- Examples:
- citalopram (Cipramil)
- escitalopram (Cipralex)
- fluoxetine (Prozac or Oxactin)
- paroxetine (Seroxat)
Amino acid transmitters
- All are non-essential amino acids (made in situ from glycolytic and citric acid cycle intermediates)
- Glutamate and aspartate are excitatory whereas glycine and GABA are inhibitory
GABA receptors
- GABA A = ionotropic receptor coupled to Cl− channel. Has modulatory binding sites for benzodiazepines, barbiturates, neurosteroids and ethanol
- GABA B = metabotropic receptor coupled to Ca2+ and K+ channels via G proteins and second messenger systems
Glutamate receptors
- NMDA receptors bind glutamate, glycine, Mg2+, Zn2+ and polyamines. Form channels that are permeable to cations (Ca2+ > Na+ and K+)
- Kainate and AMPA receptors interact only with glutamate and their specific agonists (Na+ and K+ > Ca2+)
- mGluRs are G-protein coupled receptors and trigger a second messenger cascade (eight different types of mGluRs)
Astrocytes buffer glutamate & GABA concentrations
- Glutamate is removed from the synapse by astrocyte uptake via excitatory amino acid transporters (EAAT)
- GABA is also taken up by astrocytes via GABA transporters (GAT)
- Both glutamate and GABA are catabolysed in the astrocyte to glutamine, which is then transported to the neurons for re-use
Many treatments target GABA & glutamate signalling
GABA receptor agonists are given for the treatment of seizures
• Memantine blocks the Mg2+ binding-site on the glutamate NMDA receptor
• Approved for use to treat Alzheimer’s disease in 2002
Peptide neurotransmitters
- Many types of small peptides (~100 known examples)
- Most common type of neurotransmitter in the hypothalamus
- Synthesised as large precursor proteins and transported to synaptic release site – activated by proteolytic cleavage
- Slow postsynaptic effects
- Actions terminated by extracellular proteases
- Often co-released with other classical transmitters
- Includes opioids - endorphins, enkephalins and dynorphins
- Other examples are substance P, neurotensin, vasoactive intestinal peptide (VIP), etc.
Other neurotransmitters
• Purines (ATP, GTP and others)
• Histamine
• Gases – nitric oxide (NO)
- NO is not stored in synaptic vesicles, but is made as required by an enzyme (NOS), from arginine
- NO simply diffuses from nerve terminals into adjacent cells and forms
covalent linkages to a multiplicity of targets, which may be enzymes or other targets
Inactivation presumably involves diffusion away
