Glu & Ach R Flashcards
What are the GluR families?
1) NMDA
2) AMPA
3) Kainate
4) Delta
GluR structure
Four subunits combine to form receptor
GluR modulated by
endogenous ions: Mg2+, Ca2+, Zn2+, H+
GluR roles in disease
Stroke, Epilepsy, Mental Retardation.
GluR activation steps
Closing = activation
1) Unbound clamshell is open and not active
2) Antagonists close the clamshell slightly, still no activation
3) Partial agonists (e.g. kainate) close the shell even more leading to weak activation
4) Full agonists (e.g. Glutamate) close the shell the most and strongly activating the R
With each step, efficacy is increasing
The glutamate activation is strong but not strong enough to be consistently activated, creating the activation jumps
Glutamate binding characteristics
- Computational simulation showed that free energy is released (to use for something else e.g. opening a channel) when Glu binds to closed clam shell
- Closing of the receptor is occurring by passing glutamate in a hand-over-hand manner starting on the left hand side
- Several pathways were common for this relay manner of passing Glu
- This simulation also discovered the Kon ~1*10^7 M-1 s-1
- Changing side chains slowed down the binding and unbinding rateChange in the left side caused more decrease than right side
- Conformational change by partial agonists are making extreme positions leading to decreased activation, time and space wise.
Ach Profile
First NT to be discovered
Initially, Dale showed
-Ach caused vasodilation which can be blocked by atropine
-Big amount of Ach, on the other hand, raised BP which was blockable by nicotine
AchR classes
Ach is a natural NT at 2 classes of R
- Muscarinic R – selectively activated by muscarine antagonised by atropinemuscarine is trans (chemical structure wise) in binding sites
- Nicotinic R – selectively activated by nicotine antagonised by curarenicotine is gauche in binding sites; extracellular binding sites; fast
Ach structure
flexible changing confirmations for the two receptors
AchR-nicotinicR
Type: Membrane ion channels, Fast (1ms Ach transient)
State: resting, active (open), desensitised (open but blocked)
Clearance: enzymatic (cholinesterase)
Structure:
-Extracellular binding sites are between subunits
-They have the aromatic ”cage” in the structure in the middle and amino acids from subunits of both sides contribute to the binding site.
-Arginine acts as a surrogate/substitute ligand in the “dead”
Characteristics:
Soup of subunits meaning abundance of subunits are allowing them to have various possible combination e.g. muscle, ganglionic and neuronal all have different subunits combination. Muscle being most different, gang and neuronal being similar
Subunit selectivity may be impossible – meaning Ach can bind as equally despite the difference in confirmation
Subunit composition of central R remains mysterious
Depolarising block can occur by blocking clearance, with non0hydrolysable agonists, antagonists that do not cause depol, both competitively and otherwise.
AchR-muscarinicR
Type: 7TM membrane protein, slow
Location: CNS, PNS and non-nervous tissue
Structure:
Coupled to cytoplasmic G-proteins, upon binding of Ach, beta and gamma subunit leaves to open K+ channel but the mechanism is unknown. Only know that PKC is not involved.
Characteristics:
It controls channels and enzymes
It is activated at lower concentrations than nicotinic receptors (nM to um) – however binds for longer time
Activation is slow and indirect
Cellular actions and excitability depend on the types of ion channels and enzymes that are coupled
Muscarinic & nicotinic R
good selectivity between them
Why are antagonists easier to make?
Because there job is to just bind and block the activity while agonists need to bind and cause the “right” conformational changes.
Antagonists are usually bigger allowing them to have multiple binding sites (energy efficient)
