Kruse DSA: Endocrine Receptors and Signaling Pathways Flashcards
Where does the term hormone come from?
Greek: “to set in motion”
-useless but interesting
What binds its receptor with more affinity, T3 or T4?
T3
What are the 4 major types of receptors in the body?
- ligand-gated ion channels
- GPCRs
- Kinase-linked receptors
- Nuclear receptors
What hormones will get the Galpha(s) receptor?
- B-adrenergic
- LH, FSH, TSH
- Glucagon
- PTH
- ACTH
- GHRH, CRH
What does Gas receptor do?
-stimulates cAMP
What hormones get the Gi receptor?
- alpha adrenergic
- Somatostatin
What does Gi do?
- inhibition of cAMP production
- Activation of K+, Ca2+ channels
Which hormone will bind to RTKs?
-insulin
What does the RTK IRS-1 to IRS-4 do?
-MAP kinases, PI 3-kinase, RSK
What hormones get the cytokine receptor-linked kinase like JAK and other tyrosine kinases?
- GH
- PRL
What does JAK do?
- STAT
- MAP kinase
- PI 3-kinase,
- IRS1
- IRS2
What hormone gets the Serine Kinase?
-TGF-B
What signaling pathway does the serine kinase receptor activate?
Smads
At what level are the effects of kinase-linked receptors exerted?
- gene transcription
- GPCRs are really the only ones that just modulate intracellular signaling events… all the rest regulate gene transcription somehow
What gets the RTK again?
insulin
What kind of receptor does TGF-B bind onto?
- Serine/threonine kinase receptor
- same as RTK but not with tyrosine
Which kinase-linked reeceptors lack intrinsic enzyme activity?
cytokine receptors
- they just activate cytosolic kinases
- examples include receptors for GH and PRL
What two things will bind to cytokine receptors again?
-GH and PRL
What happens to a kinase-linked receptor when the ligand binds it?
dimerization
-the end result is activation or inhibition of TF’s via phosphorylation
In a GPCR, where is the N and C terminals
- N is extracellular
- C is intracellular
What does the a subunit of GPCR do?
- binds to guanine nucleotides, activates effector ptns when bound to GTP, has enzymatic activity
- catalyzes the conversion of GTP to GDP resultin in a-subunit inactivation
What do the B and gamma subunits of GPCR do?
- they form a dimer and remain together
- membrane localization of G ptn and directs signaling such as activation of ion channels and binding sites for G ptn receptor kinases
What does the GPCR look like when it’s not activated?
- unattached GaBy trimer associated with the cytoplasmic side of the membrane
- GDP bound to the alpha subunit
What happens when the GPCR is activated?
- conformational change in cytoplasmic domain of receptor
- cause it to have high affinity for the GaBy
- GDP dissociates from alpha
- replaced by GTP
- trimer dissociates
How is signaling terminated in GPCR?
- hydrolysis of GTP to GDP
- occurs through the GTPase activity of the Ga subunit
- Ga reunites with GBy, completing a cycle
What does Gas do?
-stimulates adenylyl cyclase, causing increased cAMP formation
What does Gai do?
- inhibits AC, decreasing cAMP formation
- opens cardiac K+ channels decreasing heart rate
What does Gao do?
- limited effects of alpha subunit
- effectors not yet clear
What does Gaq do?
- activates PLC
- increases production of IP3, DAG, and cytoplasmic Ca2+
What does GBy do?
- same as for Ga subunits
- also activate K+ channels
- inhibit voltage-gated Ca2+ channels
- activate GPCR kinases
- activate mitogen-activated protein kinase cascade
Which Ga subtype is activated by cholera toxin?
- Gas
- blocks GPAse activity, thus preventing inactivation
Which Ga subtypes is blocked by pertussis toxin?
- Gai
- prevents dissocitation of GaBy complex
How is specificity achieved with GPCRs?
- molecular variation withing the Ga-subunit
- for example… Gas and Gai stimulate and inhibit the enzyme adenylyl cyclase
What are the 4 targets for G-proteins?
- Adenylyl Cyclase: cAMP
- PLC: IP3, DAG, Ca2+
- Ion channels CA2+ and K+
- Thoa/Rho kinase: smooth muscle contraction, cell growth
How is cAMP inactivated?
-hydrolysis to 5’-AMP by PDEs
What does cAMP do?
- activates Protein kinases… like PKA
- that goes on to phosphorylate stuff
What is the substrate for the membrane bound enzyme PLC?
- PIP2
- splits it into DAG and IP3
Which G ptn activates PLC
Gq
What does IP3 do?
- goes to ER and activates Ca2+ channels
- Ca2+ released into cytosol
- Gets dephosphorylated and recycled to form PIP2
What does DAG do?
- activates membrane-bound PKC
- that P’s a number of intracellular ptns
- DAG is lipophilic and remains within the membrane
Which G ptn will activate a channel after it dissociates from Gao?
the GBy part!
How is Rho activation supported?
- GEFs
- they exchange the GDP for a GTP
- inactivated by GAPs: GTPase-activating proteins… promote hydrolysis of GTP to GDP
What are some of the end effects of Rho kinase receptor?
-smooth muscle contraction and proliferation, angiogenesis, and synaptic remodeling
What are nuclear receptors bound by?
steroid hormones
-thyroid hormone is a steroid hormone
What 3 domains do nuclear receptors have?
- AF-1: activation function 1
- DBD: DNA binding Domain
- LBD: Ligand binding domain
Which domain plays a role in dimerization?
DBD
- highly conserved
- binds region upstream from the target gene
What is the thing within LBD that changes and allows recruitment of coazctivators or corepressors?
AF2: activating function 2
What are the classic steroid nuclear receptors?
- GR
- MR
- ER
- PR
- AR
What are the orphan receptors?
- those that bind to:
- retinoids
- thyroid hormone
- Vit D
- Xenobiotic
- Androstane
- Lipids
- FA’s
What is an example of a coactivator that would come with activation of a nuclear receptor?
- histone acetylase
- makes Chromatin open up
What is something that could be a corepressor?
- histone deacetylase
- causes chromatin to become tightly packed… preventing transcriptional activation
What are some common heterodimeric nuclear receptors?
- RXR
- RAR
- probably the other ones we will run into are homodimers
What is HRE
hormone response element
- the part of the DNA that is bound by the Nuclear receptor
- the gene is downstream
