Receptors and Cell Signaling

Question 1

effectors in cell signaling: what do they do

Answer 1

alter the activity of different components downstream and generate secondary messengers that elicit a particular cellular response (enzyme activity, gene expression, etc)

Question 2

how are signals terminated in cell signaling

Answer 2

removal of the signaling molecule and/or receptor or attenuation/inactivation of the signaling events

Question 3

endocrine signaling

• what is the signal
• long distance/short distance
• long term/short term

Answer 3

• hormone (ex: epinephrine)
• long-distance signaling
• short term signaling (half life is on minute scale)

Question 4

paracrine signaling

• long distance/short distance
• long term/short term

Answer 4

signal diffuses to neighboring target cell

ex: testosterone
- local signaling
- short lived signals

Question 5

how testosterone signaling works

Answer 5

leydig cells synthesize and secrete testosterone which induces spermatogenesis by acting on sertoli and germ cells

Question 6

autocrine signaling

Answer 6

secreting cells express surface receptors for the signal; or release to cells of the same type

ex: interleukin-1 promotes its own replication in immune response
ex: growth factors in cancer cells

Question 7

direct/juxtacrine signaling

Answer 7

signal binds to signaling cell which then binds to receptor on the target cell; acts like a bridge between the two cells

ex: heparin-binding epidermal growth factor
ex: immune cells

Question 8

hydrophilic signaling

• how it works with plasma membrane
• examples
• receptors involved

Answer 8

cannot penetrate the plasma membrane, the receptor has to be on the membrane; signaling molecule-receptor complex initiates the production of a second messenger molecule in the cell

epinephrine, insulin, glucagon

GPCRs and RTKs

Question 9

lipophilic signaling

• how it works with plasma membrane
• examples

Answer 9

signals can pass though the membrane of the target cell; ligand binds to receptor protein inside the cell (cytosol or nucleus)

steroid hormones, thyroid hormones, retinoids

Question 10

where can receptors be located for lipophilic signaling

Answer 10

nucleus or cytosol

Question 11

cytoplasmic receptors in lipophilic signaling

Answer 11

exist in inactive complex with HSP90; when they bind to ligand HSP dissociates and the hormone receptor complex translocates to the nucleus where it binds to the HRE in the promoter region of specific genes

Question 12

hormone response element

Answer 12

specific DNA sequence in the promotor region of specific genes; binds to hormone receptor complex in cytoplasmic lipophilic signaling

Question 13

nuclear receptors in lipophilic signaling

Answer 13

exists in the nucleus already bound to DNA; ligand will activate the complex to regulate the transcription of specific genes

Question 14

nAChR
GABAa
5-HT3
GlyR

what do these have in common

Answer 14

ligand gated ion channels

Question 15

G protein coupled receptors (GPCRs) signaling

- 4 steps

Answer 15

ligand binds to extracellular domain –> conformational changes in the GPCR

intracellular domain activates its G protein and GDP –> GTP

GTP bound G protein interacts with membrane bound effector protein –> secondary messenger

Question 16

how is GPCR signaling terminated (3 ways)

Answer 16

1. dissociation of signaling molecule
2. inactivation of the G protein
3. reduction of concentration of secondary messenger

Question 17

guanine exchange factor (GEF)

Answer 17

activates GPCR by adding a phosphate to the inactive GDP bound GPCR; GDP becomes GTP and the alpha subunit dissociates

Question 18

GTPase-activating protein (GAP)

Answer 18

accelerates the hydrolyzation of GTP into GDP, inactivating GPCR

Question 19

Gs type GPCR signaling

Answer 19

stimulates adenylate cyclase which activates cAMP –> activates PKA –> phosphorylates target proteins to alter their activity

• ex: epinephrine when it binds to the beta-adrenergic receptor
• ex: histamine

Question 20

Gt type CPCR signaling

Answer 20

activated by light; stimulates cGMP phosphodiesterase –> cleaves cGMP into 5’-GMP

type of negative signaling (the signal is on in the absence of light)

Question 21

Gi type GPCR signaling

Answer 21

inhibits adenylate cyclase; cAMP is not produced and PKA is not activated

• ex: epinephrine when it binds to the alpha-adrenergic receptor
• ex: dopmamine

Question 22

Gq type GPCR signaling

two end points

Answer 22

activates phospholipase C; breaks PIB2 into DAG and IP3

DAG –> PKC –> phosphorylation of target proteins to alter their activities

IP3 –> goes to the ER to open channels to release Ca2+ into the cytosol (calcium is the secondary signal) –> activation of Ca2+/calmodulin-dependent proteins

ex: acetylcholine

Question 23

what happens when epinephrine is bound to beta-adrenergic receptors

Answer 23

relaxation of bronchial and intestinal smooth muscle

can be used to relieve bronchospasms during asthma attack

Question 24

what happens when epinephrine binds to beta adrenergic receptor in the heart

Answer 24

causes contractions

can be used to restore cardiac rhythms after MI

Question 25

cAMP phosphodiesterase

Answer 25

hydrolyzes cAMP to AMP

Question 26

cGMP phosphodiesterase

Answer 26

hydrolyzes cGMP to 5'GMP

Question 27

how does viagra work

Answer 27

inhibits cGMP PDE which increases the concentration of cellular cGMP, leading to smooth muscle relaxation and vasodilation

Question 28

how does caffeine lead to increased heart rate

Answer 28

it inhibits cAMP PDE

Question 29

how does nitric oxide lower blood pressure

Answer 29

NO is produced in epithelial cells; diffuses to neighboring muscle and activates guanylate cyclase --> production of cGMP --> smooth muscle relaxation and vasodilation

Question 30

how does the cholera toxin work

Answer 30

covalent modification of alpha subunits ADP causes ribosylation of arginine --> decreases GTPase activity --> Gs remains active and continues to stimulate adenylate cyclase which causes overproduction of cAMP --> open Cl- channels in intestinal cells --> loss of electrolytes and water and increased diarrhea

Question 31

how does pertussis work

Answer 31

ADP ribosylation of cystine on Gi prevents activation and dissociation of alpha subunit from the G protein complex --> less inhibition of AC and overproduction of cAMP --> loss of fluids and excessive mucous in airway epithelial cells

Question 32

mechanism of water secretion in cholera

Answer 32

toxin activates AC to produce cAMP leads to secretion of Cl- causes build up of negative potential across the membrane --> secretion of Na+ --> net secretion of NaCl NaCl builds up an osmotic gradient across membrane --> water secretion

Question 33

4 types of signal desensitization

Answer 33

1. hormone levels drop, causing decreased adenylate cylase activity, decreased cAMP, and decreased PKA activity 2. phosphodiesterases removing cAMP/cGMP 3. receptor sequestration in endosome 4. receptor destruction in endosomes and lysosomes

Question 34

G protein receptor kinase (GRKs)

Answer 34

phosphorylate the GPCRs - arrestin binds to the 3rd intracellular loop and prevent G-alpha from interacting with third loop; GDP does not get converted to GTP to activate GPCR

Question 35

3 part of receptor tyrosine kinase (RTK)

Answer 35

1. extracellular domain which binds the ligand/signaling molecule 2. single alpha helical transmembrane domain 3. an intracellular domain with tyrosine kinase activity

Question 36

receptor tyrosine kinase (RTK) signaling - 4 steps

Answer 36

1. ligand binds to ECD causing dimerization 2. specific tyrosines are phosphorylated 3. phophotyrosine is recognized and bound by adapter and docking proteins (SH2 domain of Grb2) -->> either RAS dependent or RAS independent pathway 4. triggers phosphorylation of protein targets in nucleus, plasma membrane, cytoplasm --> alteration in gene transcription and protein acitvity

Question 37

what is RAS-dependent signaling facilitated by

Answer 37

mitogen-activated protein kinase family | MAPK

Question 38

GRB-2

Answer 38

adaptor protein; SH2 is a domain of GRB-2; recognizes and binds to motifs on the receptor that contains phosphorylated tyrosine in RTK signaling

Question 39

how is RTK signaling terminated

Answer 39

- degradation of signaling molecules - ligand induced endocytosis followed by lysosome degradation - accelerated RAS inactivation - dephosphorylation

Question 40

what do point mutations in RAS cause

Answer 40

lung, colon, and pancreatic cancers

Question 41

how do mutations in RAS cause neurofibromatosis

Answer 41

characterized by an inactivating mutation in neurofibromin (NF-1) gene, which normally encodes a GAP for RAS RAS uncontrollably activated pathway for nerve tissue growth --> optical glioma, macrocephaly, learning disabilities, Lisch

Question 42

what do point mutations in RAS cause

Answer 42

30%-50% of lung and colon and 90% of pancreatic cancers