Drug Targets

Question 1

Transcription factors:

• promote or inhibit what?
• defining feature?
• what is the response element?

Answer 1

• promote or inhibit the recruitment of RNA polymerase to specific genes
• defining feature is the presence of the DNA-binding domain
• response element is the specific DNA sequence the TF binds to

Question 2

GPCR ligands

Biogenic amines:

(x6)

Answer 2

acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, histamine

Question 3

GPCR ligands

Peptides/proteins:

(x4)

Answer 3

adrenocorticotropin, angiotensin, bradykinin, opioids

Question 4

GPCR Ligands

Amino acids

Answer 4

glutamate, GABA

Question 5

GPCR Ligands

Lipids

(x3)

Answer 5

leukotrienes, prostacyclin, TxA₂

Question 6

GPCR ligands

nucleotides

(x3)

Answer 6

adenosine, ADP, ATP

Question 7

Structure of GPCR:

• transmembrane domain
• N terminal domain (extracellular) often is what?
• C-terminal domain (cytosolic) contains multiple what?
• cytoplasmic loops contain?

Answer 7

• 7 TM domain formed by a single polypeptide chain
• N-terminal domain is often glycosylated
• C-terminal domain contains multiple phosphorylation sites (serine/threonine residues)
• cytoplasmic loops contain G-protein binding sites

Question 8

G-protein cycle:

-Six Steps

Answer 8

1. basal unstimulated state
2. Agonist activates receptor
3. which promotes release of GDP from the G Protein
4. Allows entry of GTP into nucleotide binding site
5. Signal terminated by hydrolysis of GTP
6. Return of system to (1)

Question 9

Classification of G-protein families based on what?

Answer 9

based on G_a subunit-induced effects

Question 10

G_s G_i G_q

-effect on adenylyl cyclase and Src tyrosine kinase

Answer 10

Gs activates all isoforms of adenylyl cyclase and Src tyrosine kinase

Gi inhibits adenylyl cyclases but activates tyrosine kinase Src

Gq activates phospholipase Cß

Question 11

cAMP second messenger pathway

Answer 11

Question 12

Ca²⁺-phosphoinositide signaling pathway

Answer 12

Question 13

Receptors w/ Intrinsic Enzyme Activity:

(x6)

Answer 13

IGF-1, Insulin, VEGF, EGF, NGF, PDGF

Question 14

Structure of RTKs

-exception to general rule

Answer 14

most RTKs possess a single polypeptide chain, but insulin and IGF receptors have 2 chains, alpha and beta, linked by a disulfide bond

-ligand-binding shows very little similarity between members of the family, but the tyrosine kinase domain is similar

Question 15

Mechanism of activation of the epidermal growth factor receptor:

• what happens upon binding?
• what happens when cytoplasmic domain becomes phosphorylated?

Answer 15

• upon binding of EGF (circle), the receptor converts from its inactive monomeric state (left) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently.
• the cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y), and their enxymatic activities are activated, catalyzing phosphorylation of substrate proteins (S)

Question 16

JAK-STAT:

• what kind of RTK?
• transmits the effect of which hormones/cytokines? (x5)

Answer 16

• it is a receptor coupled to cytosolic protein kinases
• transmits GH (somatotropin), Erythropoeietin, Leptin, Interferons, Interleukins 2 through 10, 15

Question 17

JAK-STAT mechanism

Answer 17

come back to this one

Question 18

Nuclear Receptors:

ligands: four examples

Answer 18

ligands are lipophilic molecules that can cross cell membrane

-examples include: steroids, thyroids, Vit D,A, and Lipid mediators such as FFAs and their products

Question 19

Nuclear receptors:

• lag period?
• persistence of effects?

Answer 19

produce their effects after a lag period, effects can persist after the agonist concentration has been reduced to zero

Question 20

Mechanism of steroid hormone action:

• how many domains does nuclear receptor polypeptide have?
• hsp90 binds to what?
• binding of a hormone causes?

Answer 20

• three domains
• hsp90 binds to the receptor in the absence of hormone and prevents folding into the active conformation of the receptor
• binding of a hormone (steroid) causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration

Question 21

Voltage gated sodium channels:

• which subunits?
• drug examples that inhibit these channels

Answer 21

• composed of alpha and beta subunits
• examples of drugs include local anesthetics, antiarrhythmic drugs, drugs used for epilepsy treatment

Question 22

voltage gated Ca²⁺ channels

• where are L type channels located?
• targets of what kind of drugs

Answer 22

located on cardiac and smooth muscle cells, targets of widely used drugs, calcium channel blockers or calcium antagonists (verapamil)

Question 23

Direct Ligand-Gated Ion Channels:

• define
• excitatory vs inhibitory

Answer 23

they are receptors for NTs that have an ion-conducting pore

Excitatory NTs open cation channels (ACH, Glutamate)

Inhibitory NTs open anion channels (GABA, Glycine)

Question 24

Nicotinic Acetylcholine receptors:

• activation causes what?
• structure and location

Answer 24

• activation induces inward sodium influx and membrane depolarization
• petameric receptors with two major locations: skeletal muscle and neuronal cells

Question 25

GABA-A receptors: - cause inward flux of what? - GABAmediates synaptic inhibition where? - Structure? - Target for?

Answer 25

- Anionic channels causing inward Cl- influx and hyperpolarization - mediate synpatic inhibition in CNS via these channels - Pentameric structure - target for inhalation GA drugs, IV GA drugs, Ethanol, Hypnotic/anti-anxiety benzos