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SFM Exam 1 > Receptors And Signaling > Flashcards

Receptors And Signaling Flashcards

1
Q

Describe endocrine signaling

A

Signal (hormone) is transported via blood
Example: epinephrine released by the adrenal medulla and acts on heart muscle
Long distance signaling and long lasting (half life on minute scale)
Freely diffusing signal

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2
Q

Describe paracrine signaling

A

Signal diffuses to neighboring target cell of a different cell type
Example: Leydig cells synthesize and secrete testosterone which induces spermatogenesis by acting on Sertoli cells and germ cells
Local signaling and short lived

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3
Q

Describe autocrine signaling

A

Secreting cells express surface receptors for the signal
Release to cell of the same type
Common in chemokines: IL-1 produced by T cells promote their own replication during an immune response
Action of growth factors in cancer cells

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4
Q

Describe direct/juxtacrine signaling

A

Signal binds to signaling cell which then bids to receptor on the target cell
Example: heparin binding epidermal growth factor like growth factor (HB-EGF) binds to EGF receptor
Occurs in immune cells

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5
Q

Describe hydrophilic signaling

A

Hydrophilic signals (ligands) cannot penetrate the plasma membrane
Interact with specific receptors at the cell surface
Signaling molecule-receptor complex initiates production of second messenger molecules inside the cell
Trigger a downstream cellular response
Ex: epinephrine, insulin, glucagon, etc

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6
Q

Characteristics of the second messengers created during hydrophilic signaling

A

Generally small and derived from amino acids, polypeptides, or through lipid metabolism
Shorter half lives (seconds to minutes)

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7
Q

Examples of receptors involved in hydrophilic signaling

A

GPCRs and receptor tyrosine kinase (RTKs)

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8
Q

Describe lipophilic signaling

A

Signals/ligands pass through plasma membrane of target cell and bind to specific receptor proteins inside the cell
Signaling molecule-receptor complex act as a TF
Receptors are located in the cytosol or nucleus
Long half lives (hours to days)
Several families of DNA binding factors including cytoplasmic and nuclear receptors which regulate the transcription of specific genes

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9
Q

Describe the cytoplasmic receptors in lipophilic signaling

A

Exist in inactive form complexed with HSP90
Upon ligand biding HSP dissociates
The hormone receptor complex trans locates to nucleus where it binds to a specific DNA sequence called the hormone response element (HRE) in the promoter region of specific genes

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10
Q

Describe nuclear receptors in lipophilic signaling

A

Already present in the nucleus bound to DNA

The hormone allows for interactions with additional proteins and activate the complex

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11
Q

Describe GPCR structure

A 
Extracellular domain (ECD): binds to signal 
Transmembrane domain (TM): composed of 7 alpha helices 
Intracellular domain (ICD): interacts with the G proteins
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12
Q

Broadly describe GPCR signaling

A

Singling molecule/ligand binds to the ECD and causes a conformational change in the GPCR
ICD activates its G protein by triggering exchange of GDP for GTP
Activated G protein (GPT bound) interacts with membrane bound effector protein typically an enzyme that produces a secondary messenger
Signal is terminated by various mechanisms

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13
Q

What are some general mechanisms by which a GPCR signal can be terminated?

A

Dissociation of signaling molecules, inactivation of the G protein, reduction of concentration of secondary messenger

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14
Q

GPCR signaling steps (detailed)

A

Ligand binds to GPCR
Conformational change occurs in receptor
GPCR interacts with and binds to heterotrimeric G protein
Receptor then acts as a GEF (guanidine exchange factor)
Conformation of G-alpha protein is changed such that it kicks out GDP and allows GTP to bind
Activated G-alpha binds to and activates or inhibits effector molecule
Effector molecule catalyzes reactions that produce secondary messengers

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15
Q

Which three subunits are present in heterotrimeric G protein?

A

Alpha, beta and gamma

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16
Q

What does an inactive G protein have bound to it?

A

An inactive G protein has GDP bound to its alpha subunit which is attached to the beta and gamma subunits

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17
Q

How does a G protein become active?

A

To become active the G protein must exchange its GDP for GTP which is facilitated by the GEF activity of the GPCR

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18
Q

How does a G protein return to the inactive state?

A

The intrinsic GTPase activity of the G protein hydrolyzes its bound GTP into GDP and phosphate which is accelerated by a GTPase-activating protein (GAP)

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19
Q

What is signal desensitization?

A

Ability to turn off a signal (termination step of signaling)

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20
Q

What are the different signal desensitization mechanisms?

A

Drop in hormone levels —> decreased adenylyl cyclase activity —> decreased cAMP —> decreased PKA activity
Removal of the signaling molecule: phosphodiesterase will remove cAMP/cGMP
Sequestration of receptor in endosome
Destruction of receptor: endosomes + lysosomes (proteases)

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21
Q

Gs

A

Stimulates adenylate cyclase

22
Q

GPCR signaling via Gs

A

Signal binds to GPCR
Gs-alpha binds to GTP and activates adenylate cyclase
Adenylate cyclase converts ATP to cAMP which then activates PKA
PKA phosphorylates target proteins to alter their activity
Phosphodiesterase (PDE) converts cAMP into AMP

23
Q

Gi

A

Inhibits adenylate cyclase

24
Q

GPCR signaling via Gi

A

Signal binds to GPCR
Gi-alpha binds to GTP and inhibits AC
cAMP is not produced and PKA is not activated

25
Q

Gt

A

Stimulates cGMP phosphodiesterase

26
Q

GPCR signaling via Gt

A

Light binds to GPCR

Gt-alpha binds to GTP and activates cGMP PDE which converts cGMP to 5-GMP

27
Q

Gq

A

Activates phospholipase C

28
Q

GPCR signaling via Gq

A

Signal binds to GPCR
Gq-alpha binds to GTP and activated PLC which breaks down PIP into IP3 and DAG
IP3 binds to a Ca channel and activates a Ca-calmodulin dependent protein
DAG activates PKC which phosphorylates target proteins

29
Q

What type of G protein is epinephrine (when bound to beta-adrenergic receptor) and histamine?

A

Gs

30
Q

What type of G protein is epinephrine (when bound to alpha adrenergic receptor) and dopamine?

A

Gi

31
Q

What type of G protein is acetylcholine?

A

Gq

32
Q

What type of G protein is light?

A

Gt

33
Q

What is the physiological response when epinephrine acts as a Gs and binds to a beta adrenergic receptor?

A

Relaxation of bronchial and intestinal smooth muscle
Contraction of heart muscle
Increased breakdown of TAGs in adipose, glycogen in liver and muscle, and increased glycolysis in muscle
Epinephrine non-selective agonist of all adrenergic receptors (Major subtypes earth alpha 1 and 2, beta 1, 2 and 3)
Undergo multiple GPCR signaling pathways

34
Q

What is the physiological response when histamine acts as a Gs and binds to a GPCR?

A

Bronchoconstriction and sx of allergic reactions (e.g. itchy water eyes)

35
Q

Describe hydrolysis of cyclic nucleotides

A

Enzymes hydrolyze cyclic nucleotides to regulate their concentrations in cells
cAMP phosphodiesterase (cAMP PDE) hydrolyzes cAMP to AMP
Inhibitors of cGMP PDE increase concentration of cellular cGMP which prolongs its effects for a greater amount of time
Leads to smooth muscle relaxation and vasodilation resulting in erection
Ex of cGMP PDE inhibitors: viagra, levitra, Cialis
Caffeine inhibits the activity of cAMP PDE, leading to the accumulation of cAMP leading to increased heart rate

36
Q

Explain how cholera toxin is an example of inhibition of G proteins by bacterial toxins

A

Cholera toxin prevents the inactivation of Gs-alpha*
Due to consumption of water/food contaminated with the toxin
Covalent modification of Gs-alpha subunit*
ADP ribosylation of Arg in Gs-alpha which decreases GTPase activity*
Gs-alpha remains active (GTP bound form) which continuously stimulates AC resulting in overproduction of cAMP
Over abundance of cAMP in intestinal cells results in open Cl channels*
Results in loss of electrolytes and water as well as diarrhea

37
Q

Mechanism of H2O secretion in cholera toxin infection

A

Toxin activates AC to produce cAMP which then activates CFTR*
Leads to secretion of Cl*
Builds up negative potential across the membrane and leads to secretion of Na —> results in the net secretion of NaCl
NaCl builds up an osmotic gradient across the membrane which leads to water secretion

38
Q

Describe how the pertussis toxin is an example of inhibition of G proteins by bacterial toxins

A

Pertussis toxin prevents the activation of Gi-alpha
ADP ribosylation of Cys on Gi-alpha prevents activation and dissociation of alpha subunit from the trimeric G protein complex
Less inhibition of AC and hence overproduction of cAMP*
In airway epithelial cells pertussis toxin cause loss of fluids and excessive mucous secretion which presents as whooping cough

39
Q

How is NO produced?

A

NO is produced in epithelial cells from arginine and is responsible for the relaxation of smooth muscles

40
Q

Describe NO and smooth muscle relaxation

A

NO diffuses to neighboring muscle and activates guanylate cyclase leading to the production of cGMP
CGMP produced from activated guanylate cyclase results in smooth muscle relaxation and vasodilation
Nitroglycerin and other nitrates (the medicines taken by patients with angina) decompose to form NO and help to lower BP

41
Q

Which drugs should patients who take nitrates avoid?

A

Should avoid taking drugs that inhibit cGMP PDE (ex. Erectile dysfunction drugs) as the combination can lead to extreme vasodilation and fatal drops in BP

42
Q

Explain how antihistamines inhibit GPCR signaling

A

Histamine is generated from the amino acid histidine and is a ligand that binds to four histamine GPCRs
Antihistamines are the compounds that block the effects of histamine on the H1 GPCR
Non drowsy antihistamines are designed such that they do not cross the BBB and hence do not bind to receptors in the brain which prevents you from feeling drowsy

43
Q

Describe the structural motif of receptor tyrosine kinase

A

ECD contains ligand/signaling molecule binding site
E.g. ligands—growth factors (EGF, NGF, PDGF), insulin
Transmembrane domain - single helix that spans the membrane
ICD posses tyrosine kinase activity

44
Q

Describe RTK signaling

A

Ligand binding to ECD induces conformational change that causes dimerization of the receptor
Dimerized receptor causes auto-phosphorylation of specific tyrosine residues
Phospho-tyrosines recognized by adaptor and docking proteins (SH2 domain of Grb2)
Activate downstream signaling pathways
Trigger phosphorylation of specific protein targets in nucleus, cytoplasms and plasma membrane
Leads to alterations in gene transcription and protein activity

45
Q

What are the alterations in gene transcription and protein activity that are seen in RTK signaling?

A

RAS dependent signaling facilitated by MAPK family and RAS independent signaling facilitated by different kinases

46
Q

How are RTK signals terminated?

A

Degradation of signaling molecules/ligand by extracellular proteases
Ligand induced endocytosis of receptor and its degradation in lysosomes
RAS inactivation
Dephosphorylation of protein targets by phosphatases

47
Q

What are small G proteins?

A

Monomeric G proteins
More than 150 members of the RAS superfamily of small G proteins
Play an important role in transduction of signals from membrane receptors to effector proteins
Have a signal polypeptide chain
Have intrinsic GTPas activity (mutations can lead to cancer)
Subfamilies include RAS, RAB, RHO and RAN

48
Q

What diverse processes can small G proteins control?

A

Cell proliferation, intracellular vesicular traffic, survival and apoptosis, cell shape and polarity, membrane transport and secretion

49
Q

Mutant forms of RAS or its GEFs or GAPs have been implicated in a wide range of human cancers including

A

30-50% of lung and colon and 90% of pancreatic cancers associated with activating point mutations in RAS

50
Q

Mutations in RAS decrease what?

A

GTPase activity and lock it in active, GTP bound state

51
Q

Neurofibromatosis

A

Condition marked by growth of tumors in nerve tissue

Caused by mutation in neurofibromin gene which encodes a GAP for RAS so RAS is uncontrollably activated

52
Q

Explain the role that RTKs can play in cancer

A

Excessive signaling from mutated/over expressed RTKs are associated with cancer
RTKs are the target for pharmacological inhibitors
Ex. Breast cancer drug, Herceptin targets HER2 which belongs to the family of EGF-binding RTKs

SFM Exam 1 (8 decks)

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