Lecture 4- acetylcholine and others Flashcards
How is acetylcholine made?
from choline and acetylchoenzyme a.
acetylcholinetransferase takes the acetyl and outs it on choline. Very simple step- energy efficient.
Once acetylcholine is released it’s broken down by acetylcholineesterases. About 10 times more acetylcholinestersases than receptors. so more likely to be broken down than to activate receptor.
What are the two main tracks in the brain for acetylcholine?
One running into the thalamic area, to do with locomotion
Another from nucleus basalis more to do with learning and memory.
Not a huge transmitter int he brain but peripheral in mammals. Because glutamate in the brain, acetylcholine more in neuromuscular junctions
What are the roles of acetylcholine?
Arousal, learnign and memory.
Particularly short term memory.
What happens in receptor knocout mice for acetylcholine?
There is little behavioural abnormality. This is because there is compensation. Because there are other subunits of the receptor that get upregulated. So animal adapts.
(Affects drugs because the cns can try to adapt to the change you’ve made with the drug)
What are two types of acetylcholine receptor?
- nicotinic- ionotropic.
signal increases Na+. Fast. Excitatory. - muscarine-metabotropic. signal influences K+ permeability. Mixed effect depending on which K chanel effecting. Slow.
Which group of acetylcholine receptor most important for drug targetting?
Muscarinics.
Describe the two acetycholine receptor types in more detail
Muscarinic= 5 subtypes mAChR1-5. 1,3 and 5 are excitatory via M-current. 2 and 4 are inhibitory, acting through opening of K channels or closing Ca channels.
Nicotinic-ligand gated to Na+,K+ (and a tiny bit Ca+). Pentameric structure. homo- or hetero-meric. mostly presynaptic in the CNS.Facilitating Glu release.
but biggest case where you’ll find them is neuromuscular junction in skeletal muscle.
Describe the subunits of nicotinic acetylcholine receptor
Epsilon and gamma subunits are devlopmentally regulated. epsilon more releated to adult form. fetal ones more gamma. Fetal more permeable to calcium which is why smoking may be worse for developign fetus.
Always two alphas because they have the binding sites for the acetylcholine. and need 2 for the channel to open.
Describe the nicotinic acetylcholine receptor structure?
Heteropentamer of four related subunits (a b g d).
Each subunit has a transmembrane a-helix (the M2 helix).
The five M2 helices combine to form the pore.
Each a-subunit contains an acetylcholine binding site.
Binding of acetylcholine ‘opens’ the receptor.
NOTE most ligand-gated ion channels have similar structures
How does acetylcholine cause nicotinic acetylcholine receptor to open when it binds?
When it’s closed, Inside the pore are hydrophobic amino acid groups which close off the pore.
When acetylcholine binds,conformational change. Which causes the large hydrophobic residues to be replaced by small polar residues so pore “open”.
Describe the Selectivity of the nicotinic acetylcholine receptor?
The open pore allows the passage of Na+ and K+ (Ca2+) but not Cl-.
Selection is based on charge and size.
Nicotinic Selection based on charge.
The receptor contains three rings of negatively-charged residues.
Glutamate and Aspartate residues attract cations but repel anions (Cl-).
Nicotinic Selection based on size.
The open pore has a diameter of 7 Å.
This is sufficient to allow the passage of Na+ and K+ but not so much Ca2+.
Remember - ions are surrounded by hydration shells.
Where is histamine found?
Found in immune cells called Mast cells in the brain.
Found in Magnocellular neurons in the posterior hypothalamus! (which showed that it is a Nt)
Histamine receptors?
3 types in brain: H1, H2 and H3, all G protein coupled with 7 trans-membrane domains
H1 coupled to IP3 and increases neural excitability. this is the one that keeps you awake.
H2 positively coupled to cAMP, also excitatory.
H3 – less well understood, possibly auto-receptor or hetero-receptor on other neurotransmitters
