Neuro 413

2/18/14
UNIT 3 PART A:
Drug effect-actions of the drug at receptor
Max effect- when receptor is fully occupied
Potency-ED50
Accesibility of drug to receptor
Affinity to receptor
(fill)
Affinity- Measure of tightness in which a drug binds to a receptor
-Efficacy= Bound, thus measuring the ability to make a biological effect
-Endogenous substance
- Also know as intrinsic
D+R< DR
>
K= rate of disassociation/ association
-With each other that is
K1-Rate of association
High Affinity- Bind to receptor (larger value of K1) relative to dissociation (small
value of K1)-> Greater tendency
KD- Equilibrium dissociation constant
-amount of drug needed to occupy 50% of the receptors
Small KD=higher affinity-value is higher than value for Diss
Less of the drug is needed to occupy 50% of the receptors
Units=concentration (M, mM, etc)
Drug given at KD- at 50% of receptor
Less drug is needed thus
ED50 does not equal KD
Drugs differ in their ability to produce a conformational change
Efficacy-> Receptor occupancy
-Ability of drug to activate receptor
--> Thus a conformational change occurs
--> (fill)
Agonist- Ligand that has affinity and efficacy at the receptor
-> Leads to a biological effect
-> Full= complete
-> Partial-> Not able to complete the bio effect
Antagonist- Same as Agonist, but has no efficacy
-Square block in a round hole
-> Competitive- Prevents other things from affecting the receptor. Same location
or similar to the place where NT bind, thus preventing an effect. Up the dosage,
and it will outcompete the NT
-> non competitive - Changes the receptor to fit the antagonist, but not the
original NT. Different site, thus no matter the dosage it will not activate the
receptor
So where are they binding at the receptor
More Complex effects- Partial agonist
-> Does not reach the max activity
-> No matter how much is given
Inverse agonist-> Reduces the total constitutive effect
->Normally some activity (endogenous) is occurring. Level of activity is prevented
due to binding to receptor and making the receptor inactive. Causing the receptor
to change. -> G protein
Individual receptor now
6 main types
1. Ionotropic
->Complete receptor protein is composed of 4-5 subunits
-> Make a funcitonal receptor
- Tetramer or Pentamer
-Form a pore (centralized) thus allows Ion movement
-> 1 or more binding sites for ligands
(usually at N terminus)-> changes membrane potential
Each subunit has 4 transmembrane domains (TMDs)-> unique AA makeup each
-M1 to M4
GABAa has 5 subunits-> permeable to chloride
Break
2. G protein receptor
- Metabotropic receptors
--> Most common in the brain ( > 1000)
1 Protein subunit site with 7 TMDs: Binding site-> coils of the AA sequence
Ligand binding does not equal Ion channel opening
-> Leads to activation of G-protein
Functional receptor is called a Dimer
- 2 GPCR subunits combined together
-Dimers equal a greater chance for a biological effect.
G protein Coupled Receptor
G- Guanine
A dissociable heterotrimeric complex
GDP bound alpha subunit
Beta and Gamma subunits
4 Families of subunits: Gi/o, Gs, Gq, G12/13<- Alpha
Basal state- GDP bound subunit and the Beta/ Gamma complex are associated
Ligand (agonist) binds
Conformational change occurs when agonist binds
-/Gamma can influence different enzymes, etc. <- Affectors
can also influence other places
Not meaningful if termination is possible
- GTP turing back into GDP
--> Activity of GTPases
-> Regulators of G-protein signaling (RGS)
Effectors can have GTPase activity
Return to Basal state
- GDP bound (fill)
Stimulating of inhibiting the opening of Ion channels = G protein gated ion
channel (Calcium and Potassium)
Stimulating of inhibiting effectors which in turn act on 2nd messengers
-2 main effector enzymes- Adenylyl Cyclase(AC) and Phospholipase C(PLC)
2nd messenger pathways
Effectors lead to synthesis or breakdown of 2nd messengers
- Cyclic AMP ( cAMP)
-IP3 and DAG
These then activate protein kinases
-Phosphorilation of proteins then change of their function
Can also Phospholylate proteins in the nucleus that turn off/on genes
Usually hours or longer (permanent)
transporters
- Plasma membrane transporters
-remove, or release molecules across the cell
- Sodium chloride dependant Trans.
--> 12 TMD
--> cotransport NA+ and CL with the NT -> Dopamine, Norepinephrine and
Serotonin
Sodium dependant transporters
6, 8 or 10 (?) TMDs
-co-transport of sodium and potassium
--> Glutamate
Vesicular membrane transporters
-Dependant on the movement of H+
-Localized on vesicles
- Cytoplasm to vesicles
trk Receptor
-Single AA chain with a long N terminus
Single TMD
Binding _> dimers_> trk-> Stimulated
NT actions at trk receptors
* Ligand binds
* Dimerization
*Phosphorylates each other
-At tyrosine residues
* Protein kinases activated
* Slower acting -> Long term regulation
Trk receptor
- Mediate neurotropic factor actions
- Subtypes
--> trkA= Nerve growth factors
trkB=
trkC=
Intracellular receptor
- Regulate gene expression
Zinc fingers= conserved DNA binding domain
Ligands have to enter cell -Alter gene transcription
-Slow onset
-Long term effects
Drug effects on synaptic transmission
=See slide
Autoreceptors
-Similar to Postsynatpic receptors, but location is different
-Located on the terminal
-Somatodendritic
-Mechanisms = Slow cell firing
-Actions of autoreceptors= Somatoden. -> effects on ion channels
Influence release
-Terminal, but also somatoden.
--> Alter synthesis
--> Influence calcium by changing the influence of calcium channels
Cell can release NT, but then a feedback occurs then on an autoreceptor
These were classical methods=Typical
Non-classical (atypical)
Classic- Anterograde signaling
Endocannabinoids-THC
Non-classical-> hormones
can act extrasynaptically-Membrane bound receptors
Trk receptors and GPCRs
Intracellular responses.
End of A