Receptors and Cell Signaling

Question 1

Juxtacrine signaling

Answer 1

Signal binds to signaling cell which then binds to receptor on target cell
i.e. heparin-binding epidermal growth factor

Question 2

Hydrophilic signaling

Answer 2

Signals cannot penetrate plasma membrane, bind to extracellular receptor (insulin, epinephrine)

• GPCRs
• RTKs

Question 3

Lipophilic signaling

Answer 3

Signals pass through plasma membrane of target cell (steroid hormone, thyroid hormone)
Receptors located in cytosol or nucleus

Question 4

Cytoplasmic receptors in lipophilic signaling

Answer 4

Exist in inactive form complexed with HSP 90. Upon ligand binding, HSP dissociates, and hormone receptor complex translocates to the nucleus where it binds HRE (hormone response element) in the promotor region

Question 5

Nuclear receptors in lipophilic signaling

Answer 5

Already present in nucleus bound to DNA. Hormone allows for interactions with additional proteins and activates the complex

Question 6

GPCR method of action

Answer 6

Inactive until GDP is exchanged for GTP. Once this occurs, G-alpha subunit disassociates from G-beta/gamma subunits and Ga binds and activates or inhibits effector molecule

Question 7

Ways to turn off signal

Answer 7

Drop hormone levels-decreased adenylyl cyclase, decreased cAMP, decreased PKA activity
Remove signaling molecule (phosphodiesterase removes cAMP)
Receptor sequestration in endosome
Receptor destruction in endosome+lysosome

Question 8

Gs vs Gi (types of GPCRs)

Answer 8

Gs stimulates adenylate cyclase

Gi inhibits adenylate cyclase-increased heart rate

Question 9

Gt vs Gq

Answer 9

Gt stimulates cGMP phosphodiesterase- vision

Gq activates phospholipase C- bronchoconstriction and stimulation of salivary glands

Question 10

How does Viagra work

Answer 10

Inhibits cGMP phosphodiesterase, increasing its cellular concentration and prolonging its effects, leading to smooth muscle relaxation and vasodilation- resulting in erection

Question 11

Caffeine effect on GPCR signaling

Answer 11

Caffeine inhibits phosphodiesterase, leading to cAMP accumulation and increased heart rate

Question 12

Cholera toxin and GPCR signaling

Answer 12

Covalent modification of alpha subunit of Gs
ADP ribosylation of Arg in Gsa decreases intrinsic GTPase activity
Gsa remains active (bound to GTP) and continuously stimulates adenylate cyclase, resulting in overproduction of cAMP
Overabundance of cAMP in intestinal cells open Cl channels, loss of electrolytes and water, diarrhea

Question 13

Pertussis toxin and GPCR

Answer 13

Prevents the activation of Gia
ADP ribosylation of Cys on Gia prevents activation
Less inhibition of AC and overproduction of cAMP
Causes loss of fluid in airway epithelial cells, excessive mucous secretion

Question 14

NO method of action

Answer 14

Diffuses to neighboring muscle and activates guanylate cyclase, leading to production of cGMP
cGMP causes smooth muscle relaxion, vasodilation
Nitroglycerine decomposes to form NO and helps lower blood pressure

Question 15

Patients taking nitrates should avoid what drugs

Answer 15

Drugs like Viagra which inhibit cGMP PDE, because the combination can lead to extreme vasodilation and fatal drops in blood pressure

Question 16

Antihistamine action

Answer 16

Lipophilic compounds that block the effects of histamine to the H1 GPCR

Question 17

GPCR structure vs RTK structure

Answer 17

GPCRs have 7 membrane spanning domains, RTKs only have 1

Question 18

RTK signaling method of action

Answer 18

Binding of ligand causes dimerization
Dimerized receptor phosphorylates tyrosine residues
These residues are recognized by adaptor/docking proteins which activate downstream pathways (RAS-dependent-MAPK or RAS-independent)
Both pathways lead to phosphorylation of specific targets leading to alteration in gene transcription/protein activity

Question 19

RAS and cancer

Answer 19

Many cancers are associated with mutated forms of RAS

Mutations decrease GTPase activity and lock it in active GTP bound state

Question 20

RTKs and cancer, Herceptin

Answer 20

Breast cancer drug Herceptin targets HER2, which belongs to the family of EGF-binding RTKs