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5 steps of endogenous chemical signaling
-synthesis
-release
-distribution
-binding
-removal
ACh synthesis
acetyl CoA + choline --> acetylcholine + CoA by choline acetyltransferase (ChAT)
ChAT (choline acetyltransferase)
enzyme that synthesizes acetylcholine from acetyl CoA and choline
ACh removal
ACh → choline + acetate by acetylcholinesterase (AChE)
α-NETA
drug that inhibits choline acetyltransferase (ChAT), resulting in reduced ACh synthesis
Botox (botulinum toxin)
toxin that cleaves SNARE proteins to block vesicular release of ACh, resulting in decreased synaptic ACh
neostigmine
drug that inhibits acetylcholinesterase (AChE), preventing ACh degradation resulting in increased ACh signaling
dopamine synthesis
-tyrosine → L-DOPA by tyrosine hydroxylase (TH)
-L-DOPA → DA by DOPA decarboxylase (DDC)
tyrosine hydroxylase (TH)
enzyme that converts tyrosine to L-DOPA
DDC (DOPA decarboxylase)
enzyme that converts L-DOPA into dopamine
dopamine transporter (DAT)
membrane protein on presynaptic cell that reuptakes dopamine from the synapse
AMPT
a drug that inhibits tyrosine hydroxylase (TH), resulting in decreased synthesis of catecholamines such as dopamine
amphetamine
drug that causes vesicular release of DA into cytoplasm, resulting in DA exiting the cell through DAT
cocaine
drug that blocks DAT to prevent DA reuptake from the synapse, resulting in increases DA signaling
CGRP synthesis
encoded in the genome, thus it is expressed and translated into the peptide
peptidases
enzymes that break down proteins, such as CGRP, into peptide fragments
fremanezumab
drug that binds to extracellular CGRP to reduce free peptide available
orthosteric binding site
binding site on a receptor to which the endogenous ligand binds
allosteric binding site
binding site on a receptor that is a different site from where the endogenous ligand binds
orthosteric binding
binding competes with endogenous ligand for the receptor
signaling bias
a measure of the degree to which a drug can selectively activate one signaling pathway over another signaling pathway
example of signaling bias
in MOR signaling, a lower threshold of receptor activation is necessary for recruitment of G-protein signaling versus β-arrestin signaling
allosteric binding
binding to separate site from where orthosteric ligand binds, but affects the receptor's response to orthosteric ligand (affinity or efficacy) either positively or negatively
pure allosteric modulators
allosteric modulators that have no effect on receptor activity on their own
positive allosteric modulator (PAM)
allosteric modulator that increases the net signal by orthosteric ligand by increasing its affinity or efficacy for the receptor
GABAa receptor
ionotropic, pentameric receptor for GABA that allows Cl- ions to enter the cell, thereby inhibiting cell firing; has multiple allosteric sites for benzodiazepines, barbiturates, ethanol, and neurosteroids
GABA binding site
α-β interfaces of GABAa receptor
benzodiazepine binding site
α-γ interfaces of GABAa receptors
benzodiazepines, barbiturates
______ increase frequency of GABAa receptor channel opening in the presence of GABA, while ______ prolong duration of GABAa receptor channel opening in the presence of GABA
negative allosteric modulator (NAM)
allosteric modulator that decreases the net signal by orthosteric ligand by decreasing its affinity or efficacy for the receptor
DMCM
negative allosteric modulator that is a BZ binding site inverse agonist, decreases GABA's action and inhibits BZ action
silent allosteric modulator (SAM)
allosteric modulators that bind to allosteric site on receptor but have no effect on orthosteric ligand's affinity or efficacy; act as allosteric site antagonist
flumazenil
silent allosteric modulator that is an antagonist of the BZ site but has no effect on GABA's action
allosteric agonists
allosteric modulators that have some level of agonist activity on their own
allosteric agonist signaling bias
a biased ability to increase or decrease orthosteric ligand action for different signaling pathways
ago-PAMs and ago-NAMs
positive and negative allosteric modulators that have some level of agonist activity on their own
spatial resolution (allosteric modulators)
allosteric modulators act only where the endogenous ligand is released
temporal resolution (allosteric modulators)
allosteric modulators act only when the endogenous ligand is released