Drug targets-Konorev Flashcards
The general name for an enzyme that transfers phosphate groups from ATP to a protein is __
Protein kinase
- Ser-Thr kinases
- Tyr kinases
The specific DNA sequence a TF binds to is called a ___
Response element
___ activates all isoforms of adenylyl cyclas and Src tyrosine kinase
Gs
__ inhibits AC but activates tyrosine kinase Src
Gi
___ activates PLC
Gq
List the steps in the GPCR-cAMP signaling cascade
Ligand binds receptor –> Gs activation (active G protein) –> Activate AC –> ATP to cAMP –> Activate PKA –> Activate Phosphorylase kinase –> Activate glycogen phosphorylase
DAG is a lipophilic intermediate that activates ___
Protein Kinase C
List the steps in the DAG and IP3 pathway:
Ligand binds receptor –> Activate G protein –> Activate PLC –> PIP2 activates DAG and IP3
- DAG –> PKC
- IP3 –> Releases Ca –> Ca-CaM complex
The receptors for a group of signaling molecules known as growth factors are often ___
Receptor tyrosine kinases
Receptors with RTK transmit the action of a number of ___
growth factors
-IGF-1, insulin, EGF, NGF, PDGF
the __ domain of an RTK shows very little similarity between members of the family
the __ domain of an RTK is similar between members of the family
ligand-binding
tyrosine kinase
proteins that contain a SRC homology 2 domain (SH2 domain) bind to proteins that have a ___ residue
phosphotyrosyl
___ domain binds to the phosphorylated tyrosines
__ domain binds to the proline-rich sequences
SH2
SH3
A ras protein is known as a __ GTPase
monomeric
list the components of the activation of a monomeric GTPase Ras by growth factors:
GF receptor: ___
Adaptor protein: ___
GEFs: ___
Monomeric GTPase protein: ___
RTK
Grb2
SOS
Ras
Point mutations in __ found in 90% of pancreatic adenocarcinomas
Point mutations in __ found in 70% of melanomas
Ras
Raf
binding of a NT to this type of receptor directly leads to a change in distribution of ions between extra and IC compartments
Ligand-gated ion channel
__ channels are multimeric channels that span the cell membrane and have a binding site for a NT inducing the current, and an ion-conducting pore
Ligand-gated
Excitatory NTs open __ channels, depolarize the cell and induce generation of AP in excitable cells
cation
Inhibitory NTs open __ channels causing inward flux and hyperpolarization, preventing generation of APs
anion
permeability to what ion is increased a result of the activation of a nicotinic receptor?
Mostly Na
Nicotinic Ach receptors are generally found where?
neuronal and skeletal m. cells
binding of GABA to its cognate receptor ion channel will cause influx of __
mostly Cl
Transcription factors promote or inhibit the recruitment of ___ to specific genes
What is the defining feature of Transcription factors?
RNA polymerase
DNA-binding domain
Transcription factors bind to ___regions of DNA that are usually adjacent to the ___ sequence of the regulated gene. The specific DNA sequence they bind to is called the ___
Enhancer or promoter
Coding
Response element
G-protein binding sites are located where?
Cytosol
In the DAG and IP3 pathway, what activates these 2?
Phosphatidylinositol disphosphate (PIP2)
What activates monomeric GTPases?
GEFs
What inactivates monomeric GTPases by accelerating GTP hydrolysis?
GAPs
Point mutations in __ are found in 90% of pancreatic adenocarcinomas
Ras
Point mutations in ___ are found in 70% of melanomas
Raf
What are examples of the types of drugs that inhibit GF signaling in carcinogenesis?
Monoclonal antibodies to GF receptors and their ligands
Multikinase inhibitors
JAK is found in which part of the cell?
Cytosol
Recombinant ligans (HGH, EPO, IFN, and IL-2), receptor antagonists such as pegvisomant (a GH antagonist), and drugs used in allergic and autoimmune disorders target the __ pathway
JAK-STAT
List some ligands that target nuclear nuclear receptors:
Steroids, thyroid hormones, Vit A and D, lipid mediators such as free FAs and their products
In the mechanism of a steroid hormone action, binding of a hormone ligand (steroid) causes dissociation of what?
hsp90
Binding of steroid causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration
___ channel conductance is induced by membrane potential changes and Na, Ca, and K channels are targets of drug action
Voltage-gated
__ channels are multimeric channels that span the cell membrane and have a binding site for a NT inducing the current, and an ion-conducting pore
Ligand-gated
__ do not bind NTs directly but are controlled by membrane potential
Voltage-gated
Local anesthetics (lidocaine), antiarrhythmic drugs (quinidine), and drugs used for tx of epilepsy (phenytoine) act to inhibit __
Voltage-gated Na channels
__ channels are located on cardiac and smooth muscle cells
L-type voltage-gated Ca channels
__ are receptors for NTs that have an ion-conducting pore
Direct ligand-gated ion channels
___ open cation channels, depolarize the cell and induce generation of AP in excitable cells
Excitatory NTs
List examples of Excitatory NTs
Ach and glutamate
___ open anion channels causing inward anion flux and hyperpolarization, preventing generation of APs
Inhibitory NTs
List examples of inhibitory NTs
Gaba and glycine
Activation of a nicotinic Ach receptor induces inward ___ fluxes and membrane depolarization
Na
Antagonist drugs used as neuromuscular blockers (Tubocurarine) and partial agonist drugs used for smoking cessation (Verenicline) are examples of this pentameric receptor:
Nicotinic Ach receptor
GABA-A receptors are anionic channels that cause inward __ influx and hyperpolarization. GABA mediates synaptic inhibition in CNS via these channels
Cl
This type of receptor is a target for:
- inhalation general anesthesia drugs (halothane)
- IV general anesthesia drugs (propofol)
- ethanol
- hypnotic and anti-anxiety benzodiazepine drugs (valium)
GABA-A
Volatile anesthetics and ethanol target the ___ subunit of the GABA-A receptor
Neurosteroids and propofol target the __ subunit of the GABA-A receptor
Alpha
Beta
Cardiac glycosides target the ___
Na pump
Thiazide diuretics (chlorothiazide) target the __
Na/Cl co-transporter
Loop diuretics target the ___
Na/K/Cl co-transporter
Adrenergic drugs (reserpine) target ___
VMAT
Adrenomimetic drugs (ephedrine, amphetamines) target __
NE transporter
Antidepressants (paroxetine) target )))
SERT (serotonin/Na symporter)
