Receptors And Cell Signaling

Question 1

The Leptin gene is _____________ and is the “satiety signal”

Its counterpart ___________ also acts on the hypothalamus and is named the “hunger hormone”

Answer 1

Recessive

Ghrelin

Question 2

___________ alter the activity of different components downstream a signaling event and generate secondary messengers

Answer 2

Effectors

Question 3

____________ signals are transported via blood (hormones) and are ______-lasting.

The ligand can be ______________ or stored in a vesicle

Answer 3

Endocrine
Long
Hydrophobic

Question 4

____________ signals diffuse to neighboring target cells of a different type. These are short lived, local signal molecules

Answer 4

Paracrine

Question 5

What is the main biologic example of paracrine signaling?

Answer 5

Neurotransmission

Question 6

___________ signals occur when secreting cells express surface receptors for that signal

Answer 6

Autocrine

Question 7

Growth factors in cancer cells utilize what type of signaling?

Answer 7

Autocrine

Question 8

Epinephrine released by the adrenal medulla acts on heart muscle - this is an example of what type of signaling?

Answer 8

Endocrine

Question 9

____________ refers to when signal binds to the signaling cell which then binds to receptor on the target cell. This occurs with immune cells.

Answer 9

Direct/Juxtacrine

Question 10

_________ signals freely diffuse accross PM’s

____________ signals undergo gradient-dependent diffusion

___________ signals require an active transport mechanism

_______ signals utilize ion channels

Answer 10

Hydrophobic

Small, uncharged, polar

Large, uncharged, polar

Ions

Question 11

__________ signals are lipid-soluble and diffuse freely through membranes and interact with receptors in the cytosol or nucleus

Answer 11

Lipophilic

[note that these must be bound to carrier proteins to be transported through the blood]

Question 12

What are the 2 different types of lipophilic receptors?

Answer 12

Cytoplasmic - form complex with HSP and dissociate upon signal binding, translocating it to the nucleus where it binds a DNA sequence and alters rate of transcription

Nuclear - present in the nucleus bound to DNA. Alters transcription of certain genes after signal binding

Question 13

Describe hydrophilic signals

Answer 13

Water-soluble, cannot diffuse through membrane

Bind to surface receptors and trigger downstream events

Generally small and derived from AA’s, have shorter half lives

Question 14

What are 2 types of hydrophilic receptors?

Answer 14

GPCRs - mediated by G proteins, effector proteins, second messengers, 7-alpha helices

RTKs - mediated by monomeric G proteins and protein kinases, 1-alpha helix

Question 15

What type of receptor is considered to be in the enzyme-coupled receptor class?

Answer 15

RTKs

Question 16

Epinephrine stimulates glycogen metabolism by promoting __________ secretion

If glycogen stores are depleted, ________ stimulates gluconeogenesis by inducing enzymatic transcription

Under fed conditions, ________ promotes glycogenesis and glycolysis, and inhibits synthesis of gluconeogenesis enzymes

Answer 16

Glucagon

Cortisol

Insulin

Question 17

Oral contraceptives have long half-lives and are taken daily. What type of signal molecules do they contain?

Answer 17

Lipophilic

Question 18

Epinephrine has a short half-life and is administered at the time it is needed. What type of signal does it contain?

Answer 18

Hydrophilic

Question 19

Graves disease is an autoimmune disorder in which thyroid stimulating immunoglobulin binds to and overstimulates TSH receptors, causing hyperthyroidism, including:

Decreased _________

Increased ______ and _______

Answer 19

TSH

T3 and T4

Question 20

What are the clinical manifestations and treatment options for Grave’s disease?

Answer 20

CM - weight loss, tachycardia, insomnia, pretibial myxedema, exophtalmos, goiter

TX - surgical resection of thyroid, radioactive iodine

Question 21

Describe the structural motif of GPCRs

Answer 21

ECD binds to signal

TMD composed of 7 alpha helices

ICD interacts with G proteins

Question 22

GPCRs are arranged in a _______ pattern within the membrane, contain an extracellular ________ bond

They contain conserved _______ and ______ residues as well as a C-terminus tethered to the membrane

Answer 22

Circular; disulfide

DRY; WP

Question 23

GPCRs are active in adrenergic pathways and are targets of ______________, especialle NE and Epi

Answer 23

Catecholamines

Question 24

GPCRs are canonical in structure but diverse in function. What types of ligands can they recognize?

Answer 24

Light (rhodopsin), hormones, peptides, proteins, NT’s

Question 25

The same signaling molecule may produce different physiological responses in the same targets of different cells: Binding of epi to beta-adrenergic receptors causes _______ of bronchial and intestinal smooth muscle Binding of epi to beta-adrenergic receptors causes _______ in heart muscle

Answer 25

Relaxation Contraction [binding produces same second messenger - cAMP - in both, but downstream pathways diverge resulting in diff responses]

Question 26

Trimeric G proteins have 3 subunits: ______, _____, and ______ They also have ________activity

Answer 26

Alpha, beta, gamma GTPase

Question 27

trimeric G proteins act as molecular on-off switch They are on when the ______ subunit is bound to GTP They are inactive when bound to _______

Answer 27

Alpha GDP

Question 28

_______ are proteins that activate G proteins by promoting exchange of GDP for GTP

Answer 28

GEFs (guanine exchange factors)

Question 29

______ proteins speed up the inactivation of G proteins by promoting GTPase activity

Answer 29

GAP

Question 30

With GPCRs, once the GTP-bound, alpha-subunit interacts with an effector protein to either activate or inactivate it, it can catalyze reactions that produce second messengers. What is the typical effector protein in most GPCR-related biologic processes?

Answer 30

Adenylyl cyclase

Question 31

True or false: GTP-bound means that the G protein is inactivated because the GTP must be hydrolyzed in order to provide the energy needed for that process

Answer 31

False, GTP-bound means that the G protein is activated

Question 32

Which subunit of a trimeric G protein interacts with the effector molecule?

Answer 32

Alpha

Question 33

Adenylyl cyclase generates _______ from ATP, which activates _____, which directly regulates many pathways via phosphorylation

Answer 33

cAMP | PKA

Question 34

What are 4 methods of PKA regulation?

Answer 34

1. Phosphate group can form part of structure that other proteins recognize 2. Activation/inactivation of enzymatic target protein 3. Alteration of IC localization of target proteins 4. Alterations in abundance of target proteins

Question 35

When a signal molecule binds a GPCR, activating internal G protein Gi, what is the next step?

Answer 35

Inhibition of AC

Question 36

Gt activation by light _______ cGMP phosphodiesterase, which is an important process for ____________

Answer 36

Activates Vision

Question 37

_______ cleaves PIP2 into DAG and IP3. ______ then translocates to the ER and opens ligand-gated Ca channels Increased calcium concentration causes translocation of _____ to plasma membrane where it is activated by DAG so it can phosphorylate _______/_______ of target proteins Calcium also binds to __________, which activates other downstream targets

Answer 37

PLC IP3 PKC; Ser/Thr Calmodulin [moral of the story: Gq activation by PLC activates PKC through secondary process]

Question 38

Certain enzymes hydrolyze cyclic nucleotides to regulate cellular levels. What enzyme hydrolyzes cAMP to AMP?

Answer 38

cAMP phosphodiesterase

Question 39

Certain enzymes hydrolyze cyclic nucleotides to regulate cellular levels. What enzyme hydrolyzes cGMP to 5'GMP?

Answer 39

cGMP phosphodiesterase

Question 40

Inhibitors of cGMP PDE increase concentration of cellular cGMP, leading to what physiological effect?

Answer 40

Smooth muscle relaxation and vasodilation (viagra, levitra, cialis)

Question 41

What effect does caffeine have on cAMP PDE?

Answer 41

Inhibits it, thus increasing heart rate

Question 42

Nitric oxide is produced in epithelial cells and is responsible for relaxation of smooth muscles. It diffuses into neighboring muscle and activates _______ ________, leading to the production of cGMP. What is the desired physiological effect of taking nitrates and what is a possible drug interaction?

Answer 42

Guanylate cyclase Taken to lower blood pressure. These patients should not take drugs that inhibit cGMP PDE (like viagra) which could lead to extreme vasodilation and drops in BP

Question 43

What effect do beta agonists like albuterol and epinephrine have on conditions like asthma?

Answer 43

They are beta agonists. Albuterol is hydrophilic and binds to/activates beta-adrenergic receptors They relax bronchial smooth muscle and stimulate heart muscle contraction

Question 44

What effect do antihistimines have on GPCRs?

Answer 44

Inhibitory

Question 45

Histamines, the allergy causing signal molecules derived from _________, bind to the 4 ________ residues in GPCRs

Answer 45

Histidine; histidine

Question 46

Cholera is usually contracted due to the consumption of water contaminated with the cholera toxin. This causes ribosylation of ________ residues and ________ GTPase activity.

Answer 46

Arg; decreases So Gsa remains active and overstimulated AC produces too much cAMP --> intestinal cells open Cl channels --> loss of electrolytes and water --> diarrhea

Question 47

What effect does the pertussis toxin have on G proteins?

Answer 47

ADP ribosylation of Cys on Gia prevents activation and dissociation of a-subunit from G protein complex So less inhibition of AC, and overproduction of cAMP leads to fluid loss and excess mucous in airway epithelial cells

Question 48

___________ refers to the ability to turn off or "ignore" a signal

Answer 48

Desensitization

Question 49

What are 4 possible mechanisms for signal desensitization?

Answer 49

1. Hormone levels drop (decreased AC activity, decreased cAMP, decreased PKA activity) 2. Removal of signal molecule (PDE removes cAMP/cGMP) 3. Receptor sequestration 4. Receptor destruction

Question 50

GRKs ____________ GPCRs, then ___________ binds to the 3rd intracellular loop, preventing Ga from interacting with third loop. The result is that Ga-GDP does not get converted to Ga-GTP

Answer 50

Phosphorylate | Arrestin

Question 51

Enzyme-coupled reactions occur via RTKs. First, a signal binds to the ECD and induces a conformational change that causes dimerization of the receptor. Specific tyrosine residue is phosphorylized (autophosphorylation). What is the next step?

Answer 51

Phosphotyrosine is recognized and bound by adapter and docking proteins (SH2 domain of Grb2), leading to downstream signaling pathways that are RAS dependent or independent

Question 52

What would be the result of a mutation or other allosteric effecter causing dimerization of an RTK?

Answer 52

The RTK will remain active

Question 53

________ domains are found on adaptor proteins that recognize and bind to motifs on the receptors that contain phosphorylated Tyr

Answer 53

Recognition Examples: SH2 or PTB

Question 54

What is the difference between activated Ras and inactivated Ras?

Answer 54

Ras-GTP = active Ras-GDP = inactive [regulated by MAPkinase pathway]

Question 55

What would happen if Ras were inhibited by an intracellular injection of Ras-inactivating antibodies?

Answer 55

Cell may no longer respond to some of the EC signals

Question 56

What would happen if Ras were permanently switched on?

Answer 56

Cell would begin proliferating uncontrollably --> cancer

Question 57

Given its ability to cause uncontrolled cell division if mutated, what type of gene is Ras?

Answer 57

Proto-oncogene

Question 58

Insulin signaling occurs via RTK with intermediate scaffold including _______, which binds either Grb2 (Ras dependent) or ________ (Ras independent)

Answer 58

IRS-1 | PI3 kinase

Question 59

What is the result of the Ras-dependent insulin signaling pathway?

Answer 59

Grb-2 = Ras dependent scaffold Alters gene transcription --> increased transcription of glucokinase

Question 60

What is the result of the Ras-independent insulin signaling pathway?

Answer 60

PI3 kinase = Ras independent scaffold Alters protein and enzyme activity --> increased GLUT4 movement to plasma membrane; activation of glycogen synthase

Question 61

What specific mutation occurs with Ras to turn it from a proto-oncogene to an oncogene?

Answer 61

Mutation decreases GTPase activity and locks Ras in the active, GTP-bound state

Question 62

Neurofibromatosis is related to Ras, but Ras is not the issue with this type of cancer. What is the mutation?

Answer 62

NF-1 gene, which encodes a GAP for Ras, so RAS is uncontrollably activated in pathways for nerve tissue growth

Question 63

_______ are the target of pharmacologic inhibitors in certain types of cancer. The breast cancer drug herceptin targets HER2, which belongs to this receptor family.

Answer 63

RTKs

Question 64

Insulin resistance leads to type II diabetes. One critical aspect is a loss of insulin stimulation of glucose uptake by GLUT4 transporters in adipose and skeletal tissue. Studies point to reduced activation of ____ by insulin in obese subjects. A source of impairment is probably IRS 1 and 2.

Answer 64

PKB

Question 65

What is one of the most direct routes for affecting transcription in terms of signaling?

Answer 65

JAK-STAT receptors - transmit info from EC chemical signals to the nucleus resulting in DNA transcription and gene expression These act as cytokine receptors