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Patho 2023 > Watts Set 3 > Flashcards

Watts Set 3 Flashcards

1
Q

what are the 5 classes of receptors

A

intracellular receptors
cytokine receptors
protein kinase receptors
ion channels
GPCRs

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2
Q

what are intracellular receptors

A
  • Intracellular receptors (regulate gene expression) (steroids)
    — Stimulate the transcription of genes
    – Additional non receptor receptors
    ——– Effector enzymes that regulate cellular function include membrane potential, protein phosphorylation, translation, transcription, etc.
    ———–> Kinase, cyclase, phosphatases, ubquitinases
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3
Q

what are cytokine receptors

A

simplest
- JAK-STAT pathway
- mechanism: binds, activation leads to JAK, phosphorylation to STAT, dimerizes and travels to regulate transcription
–> Examples: GHs, erythropoietin, interferons

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4
Q

what are protein tyrosine kinase receptors

A
  • Mechanism: ligands dimerize,conformational change, phosphorylation happens and recruits GRAB, leads to activation of RAS, RAS leads to transcription
    —> Examples, EGF, PDGF, insulin
  • This pathway can be turned off by blocking
  • Receptor tyrosine kinases as drug targets
    —> Lots of ways to target an receptor
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5
Q

what are the two types of ion channels

A

voltage gated and ligand gated

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6
Q

what do voltage gated ion channels do

A
  • No ligand just membrane potential
  • Bind at allosteric sites
  • In order to block we have to activate
    –> Ex: na, ca,k
  • Involved in pain, epilepsy, arrhythmias, vascular tone, neurotransmitter release
  • Channels can be regulated by phosphorylation and G proteins
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7
Q

what do ligand gated ion channels do

A
  • Many drugs act by mimicking or blocking endogenous ligands that regulate flow of ions through channels
    –> Ex: acetylcholine, gamma-aminobutyric acid, glutamate, etc.
  • When bind the signal is transmitted across membrane and alters electrical potential
  • Very fast (milliseconds)
    –> Important in rapid transfer of signals across synapses
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8
Q

what are g couples protein receptors

A
  • Very popular in human genome and largest family
  • 40% of drugs target GPCRs
  • 3 classes (A,B,C)
  • Ligands act by modulating effectors and concentrations of second messengers
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9
Q

who invented cyclic AMP in 1971

A

earl sutherland

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10
Q

what are the features of G protein activation

A
  • effectors: channels, enzymes, regulatory proteins
  • second messengers: cAMP, CA2+, phosphoinositides
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11
Q

what are the components of the signaling process for gpcrs

A

R
- extracellular ligand is detected by cell surface receptor
G
- this receptor in turn trigger activation of G protein located on cytoplasmic face of the plasma membrane
E
- activation of Galpha and Gamma/beta then changes the activity of the effector
– enzyme or ion channel
- this effector often changes the concentration of the intracellular second messengers which produce an effect
– greatly amplified response

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12
Q

what are the subtypes of G proteins

A

Gas, Gai, Gaq/11, Ga12/13, Gby

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13
Q

what is Gas effector

A

inc. adenylyl cyclase

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14
Q

what is Gas isoforms

A

gas, golf

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15
Q

what is Gai effectors

A

dec. adenylyl cyclase

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16
Q

what is Gai isoforms

A

Gai1, Gai2, Gai3

17
Q

what is Gaq/11 effectors

A

inc. phospholipase C

18
Q

what is Gaq/11 isoforms

19
Q

what is Ga12/13 effectors

A

recruit Rho guanine exchange factors

20
Q

what is Ga12/13 isoforms

A

Ga12, Ga13

21
Q

what is Gby effectors

A

dec. adenylyl cyclase
inc. ion channels (Ca and K)

22
Q

what is Gby isoforms

A

B (1-5)
y (1-13)

23
Q

what are the second messengers

A

cAMP
cGMP
calcium and phosphoinositides

24
Q

what does the second messenger cAMP do

A
  • Effector enzyme is adenylyl cyclase and enzyme that converts ATP to cAMP
  • cAMP stimulates PKA
  • Specificity of cMAP is defined by compartmentalization of signaling complexes
    — Ex: B1 adrenergic receptors for asthma
25
what does the second messenger cGMP do
- Effector enzyme is guanylyl cyclase - cGMP activates PKG - Regulated by nitric oxide - Much more specific than other messenger systems
26
what do the second messengers calcium and phosphoinositides do
- PLC results in release of phosphoinositides and diacylglycerol - Phosphoinositides result in release of calcium - Diacylglycerol active protein kinase C --> Ex: muscarinic receptors in alzheimers
27
what are kinases
phosphorylation - 800 genes in genome - unique specificity - inhibitors as drugs: --> imantinib, trastuzumab
28
what are phosphatases
dephosphorylation - 250 genes in genome - very few drugs targets ---> ex: diabetes, PD, AD, allergy and asthma
29
what is the mechanism and consequence for homologous desensitization
- Does it to itself - Rapid desensitization -- GRKs aka B-ARK -- Less responsive - Receptor uncoupling-arrestin binding - Sequestration and fate (arrestin involvement) --- Recycling (dephosphorylation) --- Degradation (lysosomal degradation)
30
what's the mechanism and consequence for heterologous desensitization
- Can do this to another receptor with kinases - non-agonist/receptor-specific - Involve signaling cascades from other receptors --- PKA or PKC phosphorylate receptor of interest - Blunt receptor response or alter G protein coupling
31
how can we use functional selectivity to design better drugs
we can use them to enhance therapeutic pathway - TRV027-AT1 biased agonist that promotes B arrestin -- Blocks vasoconstriction in HF -- Beneficial in COVID - Opioid therapy for analgesia -- B arrestin linked to tolerance and maybe respiratory depression -- Avoid this pathway -- we want the G protein pathway here
32
what is functional selectivity and its purpose in concentration response curves
- AKA agonist trafficking, biased agonism, ligand bias, differential engagement, and protein agonism - Requires the receptor couple to multiple signal transduction pathways -- G protein and B arrestin - Display selectivity for one or more pathways when compared to another pathway - Receptor binding to other pathways
33
tell me about the Diversity of Gs-AC-cAMP system for cAMP
many different pathways and combinations; very diverse
34
tell me about the Diversity of Gq-PLCAC-IP3/DAG system for calcium and phosphoinostides
Gq-linked receptors - Multiple types - Cleaves PIP2 to produce DAG that leads to protein kinase C, IP3 that leads to production of calcium
35
what are the significances of intracellular receptors
--- Significances: ----------- Has lag period and slow ----------- Cannot be altered in minutes, takes hours ----------- Effects can persist after conc. Is reduced to zero ----------- Slow turnover ----------------> May be due to high affinity
36
what is the mechanism for intracellular receptors
--- Mechanism: steroid, ligand binding domain, dna binding domain, altered transcription of gene
37
how can we measure the second messenger cAMP
Measure by: - many ways - Radioactive assays are not popular anymore

Patho 2023 (37 decks)

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