synapses and neurotranmitters 3 Flashcards
how does acetylcholine work in metabolism
-ChAT = good marker for cholinergic neurons
-Acetyl CoA produced by cellular respiration in mitochondria
-enzyme lives in cytoplasm of presynaptic cholinergic neuron
how does Acetylcholine act on nicotinic (ionotropic) and muscarinic (metabotropic) receptors
-Nicotinic (opens and allows +ve current leading to depolarisation of post synaptic neurone) (nAChRs): ACh-gated Na+/Ca2+ channel, found at neuromuscular junction, CNS
-Muscarinic (mAChRs): 5 types of GPCRs, found in CNS and autonomic nervous system. Recall Loewi’s 1921 experiment on the heart: the ‘vagusstoff’ was ACh
-M1,3,5: excitatory via Gq
-M2,4: inhibitory via Gi/o
-Brain has ~10-100x more mAChRs than nAChRs
what junction is acetylcholine a neurotransmitter of
-neuromuscular junction (NMJ)
-Nicotinic acetylcholine receptors receive the signal on muscles
-peripheral nervous system: ACh is NT used at the NMJ
-NMJ quickly gets motor nerve to reliably and quickly excite muscle
how is acetylcholine involved in pharmacology
1)Block release
-Botulinum toxin- produced by bacteria and prevents vesicular fusion by destroying SNARE proteins
-Black widow spider venom- first increases ACh release at NMJ then eliminates it. Seems to work by allowing a big calcium influx
2)Block AChE
-Nerve gas
-Organophosphate pesticides- a class of insecticide
-Alzheimer’s treatments- first neurones to die in the brain are cholinergic therefore enhancing this signalling helps elevate early symptoms
3)Activate ACh receptors
-Nicotine, muscarine (hence the names)
-Neonicotinoid pesticides
4)Block ACh receptors
-Nicotinic: curare, α-bungarotoxin
-Muscarinic: atropine
Why is atropine used to treat nerve gas poisoning
-Atropine can be an antidote for nerve gas. Also pupil dilation, increase heart rate – bc ACh used by autonomic nerves
what are monoamines synthesised from
-amino acids
what occurs with the Storage and removal of monoamines
-Packed into vesicles by vesicular monoamine transporters (VMAT)
-Removed from the synaptic cleft by re-uptake transporters (specific ones for each monoamine)
-Destroyed by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT; on postsynaptic cell; only for catecholamines, not serotonin)
what are monamine receptors mostly
-GPCRs
-NT= dopamine, rec= D1-like D1, D5, D2-like D2, D3, D4
-NT= epinephrine, norepinephrine, recs= adrenergic receptors, a and b types
-NT= serotonin, recs= 7 receptors – one is a ligand-gated Na+/K+ channel
-Different receptors activate different G-protein effectors
Different receptors are expressed in different neuron types or parts of the brain. That’s why drugs can have specific effects
how is dopamine used in motor control
-Dopaminergic neurons in the substantia nigra project to the striatum
-This ‘nigrostriatal’ pathway facilitations initiation of voluntary movement
-These neurons die in Parkinson’s disease -> motor dysfunction (tremor, rigidity)
how can Parkinson’s be treated by increasing dopamine
-TH is rate-limiting in synthesis of dopamine, so can give L-DOPA (dopamine doesn’t cross the blood-brain barrier
-tyrosine (tyrosine hydroxylate used ) -> L- Dihydroxy-phenylalanine (dopa) (dopa decarboxylase used) -> dopamine
-enhance dopamine levels by increasing product of TH
what are MAO-B inhibitors
-enzymes which destroy dopamine -> blocked = increase in dopamine therefore enhancing dopamine
why is dopamine associated with reward
-Dopaminergic neurons in the ventral tegmental area (VTA) project to the cortex and limbic system
-This ‘mesolimbic’ pathway mediates ‘reward’/‘motivation’
how do Noradrenergic neurons regulate arousal
-Small number (~12,000 per hemisphere) in the locus coeruleus (the ‘blue place’) innervate the whole brain
-Sleep/wake, attention, arousal, mood, memory, anxiety, pain, etc. (complex!)
-(Note: distinct from the role of norepinephrine in the autonomic nervous system)
what do Serotonergic neurons do
-regulate sleep/wake, mood
-Serotonergic neurons live in the Raphe nuclei, project all over the brain
how do different drugs affect monoamines
-Cocaine, amphetamines: block reuptake of dopamine, norepinephrine
-Antipsychotics: block dopamine receptors (possible side effect: Parkinson’s-like symptoms)
-Antidepressants:
=tricyclics: block reuptake of NE, serotonin
=selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine (Prozac)
=MAO-A inhibitors
how do Endocannabinoids work
-lipid-soluble, not in vesicles
-Ca2+ triggers synthesis, not vesicle fusion
-retrograde signaling (postpre)
-bind to GPCRs (the targets of the active compound in cannabis)
how do Opioid peptides (endorphins) work
-bind to opioid receptors (GPCRs)
-regulate pain (perception/emotion/cognitive)
-also regulate coughing, GI tract
-opioid receptors are the targets of morphine, heroin
how does ATP work as a NT
-often a co-transmitter
-P2X2: ATP-gated ion channels
-P2Y2: GPCRs
how does nitric oxide work as a NT
-gas, membrane-permeable
-acts on soluble guanylate cyclase, not a membrane receptor
