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Foundations 2 > 1-38/39 Receptor families and signaling > Flashcards

1-38/39 Receptor families and signaling Flashcards

1
Q

Receptor types fast to slow

A

Rapid Brief

  • Ligand gated ion channels: aka ionotropic receptors
  • GPCRS
  • Transmembrane enzyme receptor (tyrosine kinases / JAK/STATs)**
  • Cytoplasmic and nuclear receptors**

Slow sustained

**Alter gene behavior**

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2
Q

Ligand-gated ion channels

A
  • AKA ionotropic receptors
  • Excitatory receptor channels-agonists open non-selective cation channels with the Na+ entry exciting the cell: usually it is Na+ entering but it could be other cations, but Na+ moves Vm more positive to depol
    1. Acetylcholine - nicotinic receptors
    2. Serotonin - 5HT-3 receptors
    3. Glutamate - AMPA/Kainate and NMDA receptors
    4. ATP - P2X receptors
  • Inhibitory receptor channels-agonists selectively open Cl- channels: hyperpolarizes cell and makes less likely for AP to be able to fire
    1. Gamma-aino butyric acid (GABA) - GABAa receptors
    2. Glycine receptors
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3
Q

CYS-loop receptors

A

named because alpha subunits (sites of agonist binding) have loop of cysteins, 4 membrane spanning domains

  1. Ach nicotinic
  2. Serotonin 5HT3
  3. GABAa
  4. Glycine
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4
Q

Nicotinic Ach Receptors

A
  • CYS-loop, excitatory
  • initiate skeletal muscle contration, ganglionic transmission, excitatory stuff in CNS
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5
Q

Serotonin 5HT-3 Receptors

A
  • CYS-loop, excitatory
  • concentrated in CNS sites associated with the emetic response
  • Drugs in use: Ondan_setron_ (Zofran), competitive inhibitiors at 5HT3 receptors used to tx nausea vomitting (esp in cancer pts)
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6
Q

GABAa Receptors

A
  • Inhibitory, CYS-loop
  • main inhibitory receptor in CNS, uses GABA as Neurotrans
  • ligand-gated Cl- channel
  • Drugs:
    • Benzodiazepines: azepam or azolam
      • ​7 membered ring with 2 nitrogens=benzodiazepine ring
      • positive allosteric modulator of the GABAa receptor
      • treat anxiety, produce sleep, reduce muscle spasms
    • ​Zolpidem (Ambien): sleep aid, not a benzodiazepine structurally but acts selectively at a subset of benzo binding sites
    • Penicillin: major side effect by targeting the GABAa receptor and blocks the Cl- channel once the channel is opened by GABA produces excitation: seizures, uncompetitive inhibitor
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7
Q

Benzodiazepines

A
  • Benzodiazepines: azepam or azolam
  • ​7 membered ring with 2 nitrogens=benzodiazepine ring
  • positive allosteric modulator of the GABAa receptor
  • treat anxiety, produce sleep, reduce muscle spasms
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8
Q

Glycine receptor

A
  • CYS loops, inhibitory
  • major inhibitory transmitter in spinal cord and only NT that acts exclusively on ligad-gated channels
  • Drugs
    • Strychnine: competitive inhibitor of glycine recptors, causing excessive spasticity
    • Tetanus toxin: blocks glycine relase causing excessive spasticity
  • Disease: familial startle disease of hyperekplexia
    • due to mutaitons in the alpha subunit of glycine receptor
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9
Q

Penicilin vs. GABAa receptors

A
  • Penicillin: major side effect by targeting the GABAa receptor
  • and blocks the Cl- channel once the channel is opened by GABA produces excitation: seizures
  • uncompetitive inhibitor
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10
Q

Non-CYS loop receptors

A
  1. Glutamate: major excitatory NT in CNS
    • ligand-gated ion channels two groups: NMDA receptors and non-NMDA (AMPA and kainate)
      • AMPA receptors: fast synaptic tranmission in CNS cause depolarization vai Na+ entry thru non-selective cation channels opened by glutamate
      • NMDA receptors: glutamate-gated “calcium” channels (other cations can also permeate), mediate learning and memory when normal levels of Ca+2 enter the cell, can cause excitotoxicity implicated in alzheier’s disease when excess ca+2 enters cell, responsive to glutamate and depolarization Mg+2 is stuck in channel so depol by some other channel is needed to kick out Mg+2, needs glycine to be fully activated
  2. P2X receptors:
    • appear early in vertebrate development
    • invovled in every stage of wound healing
    • over abundamnt in diseased bladder, cause of overactive bladder
    • binds ATP and then allows ion flow
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11
Q

NMDA receptors

A
  • non-cys loop, glutamate-gated “calcium” channels (other cations can also permeate)
  • mediate learning and memory when normal levels of Ca+2 enter the cell
    • can cause excitotoxicity implicated in alzheier’s disease when excess ca+2 enters cell
  • responsive to glutamate and depolarization BUT Mg+2 is stuck in channel so depol by some other channel is needed to kick out Mg+2
  • needs glycine to be fully activated
  • Drugs: memantine (Namenda) open channel blocker of NMDA receptors used to tx Alzhemier’s
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12
Q

hyperekplexia

A
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13
Q

AMPA receptor

A
  • NON-cys loop family
  • fast synaptic transmission in the CNS casues depol via Na+ entry thru non selective cation channels
  • opened by glutamate
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14
Q

P2X receptor

A

ATP release:

  • ATP is primitive NT
  • ATP is stored innerve endinds with Ach and catecholamines and is relased all together when nerves are excited
  • ATP and ADP are released drom damaged tissues

P2X ATP receptors:

  • appear early in vertebrate development
  • invovled in every stage of wound healing
  • over abundamnt in diseased bladder, cause of overactive bladder
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15
Q

Glutamate family receptors

A

Glutamate: major excitatory NT in CNSligand-gated ion channels two groups: NMDA receptors and non-NMDA (AMPA and kainate)

AMPA receptors: fast synaptic tranmission in CNS cause depolarization vai Na+ entry thru non-selective cation channels opened by glutamate

NMDA receptors: glutamate-gated “calcium” channels (other cations can also permeate), mediate learning and memory when normal levels of Ca+2 enter the cell, can cause excitotoxicity implicated in alzheier’s disease when excess ca+2 enters cell, responsive to glutamate and depolarization Mg+2 is stuck in channel so depol by some other channel is needed to kick out Mg+2, needs glycine to be fully activated

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16
Q

GPCRs general

A
  • largest family of proteins targeting drugs in clinical use
  • metabotropic receptors- because act via secondary/tertiary messenger sunstances NOT ion channels
    • Inhibitory via ion channels opening
    • synthesis of second messengers
    • phosphorylation
  • 2 components in GPCR signaling
    • THE RECEPTOR: changes conformation after binding of agonist which in turn activates the receptor partner (G-protein) (exchange of GDP bound to alpha subunit for GTP
    • THE GTP-BINDING PROTEIN: 3 subunits
      • Alpha: GDP bound (inactive), once exhanged for GTP (active) dissociated from beta/gamma subunits and initiate biological responses (Phospholipase C, adenylyl cyclase, generate synth of secondary messengers)
      • Beta/Gamma:linked, usually inhibitory of cell function
17
Q

GPCR: inhibitory motif

A
  • Mediated by Gbeta/gamma subunits
  • mechanisms include: activating K+ channels, inhibiting Ca+2 channels, decreasing cyclic AMP levels
  • receptors often have subscript 2
  • second fastest binding motif
  • membrane-delimited process
18
Q

GPCR: smooth muscle contraction

A
  1. agonist binds GPCR
  2. conformational change, G-alpha-GDP exchange to G-alph-GTP
  3. G-alpha-GTP activates PLC
  4. PLC using PIP2 as substrate produces water soluble (IP3) and lipid soluble products
  5. IP3 causes Ca+2 release from the ER and smooth muscle contraction

Receptors that signal like this often have odd number sucsripts

19
Q

GPCR: mediated phosphorylation

A
  • PKA pathway: via activating from Galpha-S
    • ex: Beta adrenergic receptors activated and Gs activated adenylyl cylcase and ATP is converted into cAMP, cAMP activates PKA which phosphorylates substrates to produce biological effects
      • phosphatases and phosphodiesterases significant in response
  • PKC pathway: via activating from Galpha-Q
    • ​ex: GalphaQ activates PLC which,
      • water soluble: synthesizes IP3 from PIP2 and evokes Ca+2 relases
      • lipid soluble: syntehsizes DAG from PIP2 which activates PKC, PKC activation then elads to phosphrylation of targets and can enhance the water soluble path
20
Q

GPCR: metabotropic glutamate receptors and GABAb receptors

A

look like a venus flytrap

21
Q

Agonist / Ion channel / GPCR

  • ACH
  • 5HT
  • GABA
  • Glycine
  • Glutamate
  • ATP
  • Catecholamine
  • Adenosine
  • Opioid
A
22
Q

Transmembrane enzyme receptors (overview)

A
  • require dimerizes confirugation beore signaling can ensue
  • Receptor tyrosine kinases (RTKs): Growth factors
  • After dimerization and reciprocal phosphorylation, P scaffold associations to initiate Kinase Kinase Kinase reactions which will result in alertered gene behavior and biological response

Types

  1. PI-3-K/AKT/mTOR (Insulin)
  2. RAS-MAPK (Growth factors)
  3. JAK-STAT (interleukins)
23
Q

Growth factor receptors

A
  • are Recetpro Tyrosine Kinases
  • EGF, TGF-alpha, (released from cell types involved in wound healing) PDGF, FGF, VEGF
  • WORK THROUGH MAPKS
  • EGF: helpful to heal wounds, harmful to metastisize cancers
24
Q

Insulin receptor

A
  • Insulin released from pancreatic beta cells in response to excessive gluce on blood stream
  • Insulin bind RTKs on other cells to promote storage of glucose/fuels
  • Insulin recpetors are present in a dimerized form in the absence of insulin-agonists
  1. insulin binds receptor
  2. kinases reciprocal phosphorylate
  3. scaffold recruited (mediates RAS/MAPKinase pathway-> cell proliferation)
  4. other scaffold, Insulin Receptor Substrate recruited ->PI3K->AKT->mTOR->mRNA/protein translated->glucose uptake/glycogen synthesis/fat storage
25
Q

Cytokine signaling

A

bind to transmembrane receptors, without tyrosine kinases of their own, that are linked in the cytoplasm via JAK/STAT pathway

JAK: cytoplasmic kinase

STAT: signal transducer and activator of transcription, bind to phosphohrylated JAK and gets phosphorylated, dimerizes and enters nucleus to alter gene transcription and coordinate immune response

26
Q

Cytoplasmic/Nuclear Receptor signaling

A
  1. Steroids / Glucocorticoids
  • steroid can pass through cell membrane to bind glucocoritcoid receptor in cytoplasm
  • dimerize of steroid-glucocoritocid receptor
  • binds DNA in nucleus to change gene transcription
  • Inhibits inflmmatory cells, inhibits syn/release of inflam mediators
  1. Environmental contaminantes/ herbal remedies (eg. st. john’s wort)
    * bind cytoplasmic receptor, binds DNA, results in enzyme induction, induce drug metabolizing enzymes, SIDE AFFECTS
27
Q

Glucocorticoid receptor

A
  • cytoplasmic, slowest of receptor types, most sustained response
  • bound by steroids
  • steroid can pass through cell membrane to bind glucocoritcoid receptor in cytoplasm
  • dimerize of steroid-glucocoritocid receptor
  • binds DNA in nucleus to change gene transcription
  • Inhibits inflmmatory cells, inhibits syn/release of inflam mediators
28
Q

Tachyphylaxis

A

tachyphylaxis: responses to acute repeated injections delcines when the interval is shortened

continuous drug application: receptor desensitization

  • ex: continuous GABA or Ach application, ionic current plateaus off because there is changing of subunit confirmation of ligand gated channels (100 ms)
  • ex: continous Glutamate on AMPA receptors: desensitizes over the tiem of their normal activation (2 ms)
  • ex: GPCRs: 10 minutes desensitization, receptor degredation from the membrane -> lysosome
29
Q

GPCR agonist desensitization scheme

A

repeated or prolonged dosing, receptors move to lysosomes and are downregulated and now resensitized

30
Q

Receptor Tyrosine Kinases agonist desensitization scheme

A

quick response, quick desensitize (2 hoursish) via internalization of receptors

31
Q

Insulin receptor desensitization scheme

A

half max response within 8-16 hours via receptor internalization

32
Q

JAK/STAT receptor desensitization scheme

A

half max wthin 4-8 hours from cytokine signaling, via receptor internalization

33
Q

glucocorticoid receptor desensitization scheme

A

half max wthin 4-8 hours from cytokine signaling, via receptor internalization

34
Q

competitive antagonists effect on receptors

A
  • continual use leads to upregulation of receptors
  • discontinuuation of the drug can lead to rebound effects
    • particularly noteworthy with drugs that antagonize GPCRs
35
Q

allosteric activators effect on receptors

A
  • frequently will NOT stimulate the receptor by itself
    • spatial/temporal harmony with natural agonist and less side effects likely
  • reduced likelihoodof receptor desensitization
    • ​ex: Zolpidem (Ambien) allosteric activator of GABAa can be prescribed for sleep aid for years
36
Q

Biased ligands at GPCRs

A
  • Specific ligands can bias their effects to activate GPCR signaling over arrestin or vice versa instead of doing both
  • B-arrestin responsible for desensitzation
  • biased ligands change conformation of GPCR so diff phosphory patterns via GRKs occur, “bar code hypothesis”, different GRKs establish unique phosphoryl barcosd which in turn recuti beta arrestins in distint conformation to bias the downstream response in one direction or another
  1. Morphine acts on Mu Opiod Receptors (MORs), beta arrestin desensisitzes and is bad and gives all the side effects
  2. Cardiovascular effects of angiotensin 2 receptors via AT1R, -sartans are unbiased ligands, b arrestin important drug target for therapy
  3. cardioprotective effects of beta blocking drugs, EPI, NOREPI signal onto Beta-1, carvedilol, beta blocker, beta arresin mediates cardoprotection
37
Q

Barcode hypothesis

A

different GPCR ligands induce diff confomrational changes so that different GRKs are activated and give unique downstream phosplhrylation and activating, bias the direction of singaling in one direction or another

Foundations 2 (27 decks)

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