Molecular Signaling

Question 1

endocrine

Answer 1

signal transported in blood long-distance, long-lasting, freely diffuses

Question 2

paracrine

Answer 2

signal diffuses to neighboring target cell of a different cell type, local signaling, short lived

Question 3

autocrine

Answer 3

secreting cells express surface receptors for the signal

ex. interleukin 1, release to cells of same type or near by, common in chemokines

Question 4

direct/juxtacrine

Answer 4

bind to signaling cell which then binds to receptor on the target cell

ex: heparin binding to epidermal growth factor

Question 5

hydrophilic signaling

Answer 5

do not penetrate plasma membrane but interact with specific receptors at cell surface

Question 6

examples of hydrophilic signaling

Answer 6

epinephrine, insulin, glucagon

Question 7

signaling molecule for hydrophilic signaling

Answer 7

receptor complex initiates production of second messenger molecules insude cells

trigger downstream cellular repsonses

Question 8

receptors involved in hydrophilic signaling

Answer 8

G protein-coupled receptors

receptor tyrosine kinase

Question 9

lipophilic signals pass through the

Answer 9

plasma membrane of target cells

ex. steroid, thyroid, retinoids

bind to specific receptor proteins inside the cell

Question 10

the signaling molecule for lipophilic signaling is

Answer 10

receptor complex that acts as a transcription factor

Question 11

cytoplasmic receptors

Answer 11

inactive form complexed with HSP 90

hormone receptro complex translocates to nucleus where it binds to specific DNA sequence called hormone response element

Question 12

nucleear receptors

Answer 12

already present in nucleus bound to DNa

the homrone allows for interactions with additional proteins and activate the complex

Question 13

both cytoplasmic and nuclear receptors regulate

Answer 13

transcription of specific genes

long half lives (hours to days)

Question 14

GPCR

Answer 14

structural motif

extracellular domain for signaling

transmembrane domain with 7 a-helices

intracellular domain-interacts with g proteins

Question 15

GPCR signaling

Answer 15

trimer G protein with three subunits (aBy)

ligand binds receptor

conformational change

GPCR interacts with G protein

Receptor then acts as GEF-guanine exchange factors

inactive G protein has GDP, to be active, must exchange it for GTP

GTP-a separates from By and activates or inhibits effector molecule

effector molecule catalyzes reactions that produce secondary molecules

intrinsic GTPase activity of the G protein hydrolzes GTP to GDP to inactivate the G protein again

activation accelerated by GTPase ativating protein (GAP)

Question 16

signal desensitization by

Answer 16

drop in hormone levels

decrease in adenylylyl cyclase-decreases cAMP-decreases PKA

Question 17

signal desensitization by

Answer 17

phosphodiesterase removinh cAMP/cGMP

Question 18

signal desensitiization by receptor sequestration and preceptor destruction

Answer 18

either by endosomes or endosomes and lysosomes as proteases

Question 19

Gs stimulates

Answer 19

adenylate cyclase

Question 20

Gt stimulates

Answer 20

stimulates cGMP phosphodiesterase

Question 21

Gi inhibits

Answer 21

adenylate cyclase

Question 22

Gq activates

Answer 22

phospholipase C

Question 23

GPCR with signaling via Gq, PLC, PKC (fig 7.5) and

Answer 23

book

Question 24

hydrolysis of cyclic nucleotides

Answer 24

enzymes hydrolyze cyclic nucletoides to regulate their cellular levels

cAMP phosphodiesterase hydrolyzes cAMP to AMP

• cGMP phosphodiesterase: hydrolyzes cGMP to 5’GMP*
• inhibitors of cGMP PDE increase concentration of cellular cGMP and prolongs its effects for a greater amount of time leading to smooth muscle relaxation and vasodilation resulting in erection (viagra, cialis)*

caffiene inhibits PDE leading to accumulation of cAMP, increasing heart rate

Question 25

inhibition of G proteins by bacterial toxins: Cholera

Answer 25

cholera toxin prevents the inactivation of Gsa cholera illness by consumption of contaminated water * covalent modification of a subunit of Gs* * ADP ribosylation of Arg in Gs a decreases intrinsic GTPase activity* * Gsa remains active GTP bound form and continuously stimulates adenylate cyclase, resulting in overproduction of cAMP*

Question 26

Overabundance of cAMP in intestince causes

Answer 26

cell opens Cl channles and loss of water and electrolytes happens cAMP activates the CFTR and secretes the Cl which leads to water secretion

Question 27

inhibition of G proteins by bacterial toxins: Pertussis

Answer 27

* Pertussis toxin prevents the activation of Gia ADP ribosylation of Cys on Gia prevents actication and dissociation of a subunit from teh trimeric G protein complex* * Less inhibition of AC and hence overproduction of cAMP* in airway, pertussis causes loss of fluids and mucous secretion increase presents as whooping cough

Question 28

nitric oxide diffuses to

Answer 28

neighboring muscle and activates guanylate cyclase, leading to production of cGMP cGMP produced from activated guanylate cyclase resulting in smooth muscle relaxation and vasodilation NTG and other nitrates decompose to form NO and help lower BP should not take cGMP PDE inhibitors (erectile dysfunction drugs) with NO because it can cause extreme vasodilation and fatal BP drop

Question 29

histamine and antihistamine

Answer 29

histamines are made from histidine which is a ligand that binds to four histamine GPCRs antihistamines are lipophilic compounds that block the effects of histamine to the H1 GPCR

Question 30

RTK motif

Answer 30

extracellular domain with signaling molecules single helix intracellular domain posses tyrosine kinase activity

Question 31

RTK signaling

Answer 31

signal binds to ECD inducing a conformational change tyrosine is autophosphorylated phosphotyrosine recognized by adapter and docking p (SH2 domain of grb2) triggers phosphorylation of protein targets leading to alteration in gene transcription and protein activity -this is either ras dependent or ras independent RTK signaling is terminated by several ways (degradation, endocytosis, lysosomal degradation, accelerated ras inactivation, dephosphorylation

Question 32

ras dependent signaling

Answer 32

facilitated by mitogen activated protein kinase (MAPK) faily

Question 33

ras independent singaling

Answer 33

facilitated by a different kinase (NOT MAPK)

Question 34

many signaling molecules are

Answer 34

protooncogenes that can mutate into oncogenes

Question 35

Monomeric G proteins

Answer 35

small g protein part of RAS familt very differnt from the trimeric G proteins in GPCR monomeric G proteins have a single polypeptide chain control a diverse process: cell proliferation, intracellular vesicular traffic, survival, apoptosis, shape, transport have intrinsic GTPase activity, mutations here can cause cancer include RAS, RAB, RHO, RAN

Question 36

RTKs in cancer

Answer 36

excessive signaling from mutated/overexpressed RTKs associated with cacner RTKs are the target of pharm. inhibitors breast cancer drug herceptin targets HER2 in the EGF-binding RTKs

Question 37

Ras in cancer

Answer 37

mutant forms of ras or GEFs or GAPs implicated in many cancers half of lung and colon and 90% of pancreatic cacners associated with activating point mutations in RAS mutations decrease GTPase activity and lock it in active GTP-bound state ex. neurofibromatisis caused by inactivating mutation in NF-1 gene which encodes GAP for RAS. here RAS uncontrollably activated pathways for nerve tissue growth