(4) Receptors and Cell Signaling Flashcards
What are the 4 types of signaling?
- Endocrine
- Paracrine
- Autocrine
- Juxtacrine
Describe ENDOCRINE signaling
Signal (hormone) is transported via blood
- Long distance signaling
- Long lasting
What is an example of endocrine signaling?
Epinephrine
Describe PARACRINE signaling
Signal (paracrine factor) diffuses to neighboring target cell of a different cell type
What is an example of PARACRINE signaling?
Testosterone
Describe Autocrine signaling
Secreting cells express surface receptors for the signal (aka, release to cells of same type)
What is an example of Autocrine signaling?
Interleukin-1
Describe Direct/Juxtacrine signaling
Signal binds to signaling cell which then binds to receptor on the target cell
What is an example of direct/juxtacine signaling?
Heparin-binding epidermal growth factor
CORRELATION BOX:
What does Insulin do?
- Lowers blood glucose by promoting glycolysis
- Inhibits gluconeogenesis
- Stimulates glycogen synthesis
CORRELATION BOX:
What does glucagon do?
- Increases blood sugar by promoting breakdown of glycogen in liver
- Inhibits glycogen synthesis
CORRELATION BOX:
What does Epinephrine do?
Stimulates glycogen breakdown by promoting glucagon secretion
CORRELATION BOX:
Cortisol?
Stimulates gluconeogenesis
CORRELATION BOX:
What is GRAVES disease biochemical impact?
- Autoimmune disorder
- Thyroid stimulating immunoglobin (TSI) binds to and OVERSTIMULATES TSH receptors –> HYPERTHYROIDISM
- Decreased TSH, Increased T3 and T4
CORRELATION BOX:
What is GRAVES disease symptoms?
- Most common amongst women, presents by 40
- Weight loss, tachycardia, insomnia, ppretibial myxedema, opthalmopathy, thyroid goiter
CORRELATION BOX:
What is GRAVES disease TREATMENT?
- Surgical resection of the thyroid gland
- Radioactive Iodine
- Pharmacological intervention
What are the types of signaling molecules?
- Water soluble (hydrophilic)
- Lipid soluble (hydrophobic)
Hydrophilic Signaling:
How does the signal communicate with the receptors?
Interacts with receptors at the CELL SURFACE
*can’t penetrate pm
Hydrophilic Signaling:
What are examples?
Epinephrine
Insulin
Glucagon
Hydrophilic Signaling:
What happens after signal binds to receptor?
Initiates production of second messenger molecules inside cell
Hydrophilic Signaling:
What are examples of receptors involved in hydrophilic signaling?
- G-protein coupled receptors (GPCRs)
- Receptor tyrosine kinases (RTKs)
Lipophilic Signaling:
How do lipophilic signals interact with their receptors?
Pass through pm of target cell
Lipophilic Signaling:
What are examples of lipophilic signaling hormones?
- Steroid hormones
- Thyroid hormones
- Retinoids
Lipophilic Signaling:
Signaling molecule-receptor complex acts as…
transcription factor
What are the three classes of receptors?
- Ligand-gated ion channels
- G protein-coupled receptors
- Enzyme-coupled receptor class: receptor tyrosine kinases (RTKs)
CORRELATION BOX: Lipophilic and Hydrophilic Hormone Medications
Give example of Hydrophilic medication
*short half lives
Epinephrine ; given at time of need
CORRELATION BOX: Lipophilic and Hydrophilic Hormone Medications
Give example of Lipophilic medication
*long half lives
Oral contraceptives
G Protein Coupled Receptors (GPCRs)
Describe the structural motif
- Extracellular domain (EDC) : binds to signal
- Tran Membrane (TM) domain: 7 alpha helices
- Intracellular Domain (ICD): interacts with G proteins
G Protein Coupled Receptors (GPCRs)
What is the order of GPCR signaling?
GPCR –> Trimeric G protein –> Effector enzyme –> 2nd messenger –> Targets of 2nd messenger –> Biological response
G Protein Coupled Receptors (GPCRs)
Trimeric G proteins contain what subunits?
3!
Alpha, Beta, Gamma
G Protein Coupled Receptors (GPCRs)
An inactive G protein has a _____ bound to it’s alpha subunit
GDP
G Protein Coupled Receptors (GPCRs)
How does the G protein become active?
Exchange GDP for GTP
*USES GUANINE NUCLEOTIDE EXCHANGE FACTOR (GEF)
G Protein Coupled Receptors (GPCRs)
What helps return the G protein to it’s inactive state?
GTPase-activating protein (GAP)
What does Gs do?
Stimulates adenylate cyclase
What does Gt do?
Stimulates cGMP phosphodiesterase
What does Gi do?
Inhibits adenylate cyclase
What does Gq do?
Activates phospholipase C
Receptor Tyrosine Kinase (RTK)
Describe the structural motif of receptor tyrosine kinases
- EDC contains signaling molecule binding site
- Single helix that spans membrane
- ICD that possesses tyrosine kinase activity
Receptor Tyrosine Kinase (RTK)
Binding of ligand causes…
dimerization
Receptor Tyrosine Kinase (RTK)
Dimerized receptor…
phosphorylates tyrosine residues
Receptor Tyrosine Kinase (RTK)
Phospho-tyrosines are recognized by ______ and _____ which activate downstream signaling pathways
Adaptor; Docking proteins
*RAS dependent, RAS independent
Receptor Tyrosine Kinase (RTK)
RAS-dependent signaling factilitated by ______ family
MAPK
CORRELATION BOXES:
RAS and Cancer
- Mutant forms of RAS (or it’s GEFs or GAPs) have been implicated in LOTS of cancers
- Mutations decrease GTPase activity and lock it in active GTP bound state
What G protein can Epinephrine bind to?
Gs or Gi
What is the importance of Epinephrine with Gs?
Epi binds to BETA-ADRENERGIC RECEPTOR;
EPI is a nonselective agonist of all adrenergic receptors
What G protein does Histamine bind to?
Gs
What does Dopamine bind to?
Dopamine D2 receptor; Gi
What binds to Gq?
Acetylcholine
What does Acetylcholine bind to?
Muscarininc acetylcholine M3 receptor; Gq
What happens when light hits rhodopsin (Gt)?
Vision
What is Viagra?
Inhibitor of cGMP PDE;
increase concentration of cellular cGMP leading to smooth muscle relaxation and vasodilation
What does NO do in relationship to smooth muscle relaxation?
NO diffuses to neighboring muscle and activated guanylate cyclase, leading to production of cGMP
cGMP produced from activated guanylate cyclase leading to smooth muscle relaxation and vasodilation.
CORRELATION BOX:
Cholera toxin:
Prevents inactivation of Gprotein; TURNED ON!!!
- Covalent modification of alpha subunits ADP ribosylation of Arg, decreases GTPase activity
- G(s alpha) remains active and continuously stimulates ADENYLATE CYCLASE resulting in TOO MUCH cAMP
-Too much cAMP opens Cl- channels, loss of electrolytes and water –> Diarrhea
CORRELATION BOX:
Pertussis (Whooping cough)
-G(i-alpha)
TOO MUCH cAMP
- LESS INHIBITION of AC
- Loss of fluids and excessive mucous in airway epithelial cells
What is signal desensitization?
Ability to turn off or ignore a signal
How can you induce SIGNAL DESENSITIZATION?
- Receptor sequestration: endosome
- Receptor destruction: endosomes + lysosomes
GRKs:
What are G protein Receptor Kinases?
GRKs phosphorylate the GPCR
Allows arrestin to bind to phosphorylated GPCR
RESULT: G-alpha-GDP does not get converted to Galpha-GTP, i.e. INACTIVATED G-PROTEIN complex
RAS-dependent signaling facilitated by ________
MAPK
RAS-independent signaling facilitated by ________
different kinase
CORRELATION BOX:
RAS and Cancer
Mutant forms of RAS or it’s GEFs or GAPs have been implicated in wide range of human cancers
CORRELATION BOX:
RTKs and Cancer
RTKs are the target of pharmacological inhibitors. Excessive signaling from mutated/overexpressed RTKs associated with cancer
HER2
