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Y1 - Pharm > 4 - Receptors > Flashcards

4 - Receptors Flashcards

1
Q

four major types of receptors?

A

G - TLC

  • G-protein-coupled receptors (GPCRs), aka seven transmembrane receptors (7-TMRs)
  • receptor Tyrosine kinase
  • Ligand-gated ion channels
  • Cytosolic receptors
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2
Q

GPCR aka Seven-transmembrane receptors (7TMRs);

  • type/quantity,*
  • purpose in pharm*
A
  • ~800 GPCRs in human genome (350 are odorant receptors)
  • 50% of clinically used drugs act on GPCRs (DIRECT OR INDIRECT)
    • 7TMRs are important targets for drug discovery
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3
Q

GPCR aka Seven-transmembrane receptors (7TMRs);

G-protein cycle

A
  1. GPCR receives an extracellular stimulus (e.g. light, calcium, odorants, pheromones)
  2. induces conformational change in receptor –> facilitating/or inhibiting coupling of receptor to G-protein (w/ alpha, beta, or gamma subunit)
    • (agonist-receptor complex activates Guanine-nucleotide binding proteins aka G proteins)
  3. G-protein heterotrimeric complex then interacts w/ diverse group of effectors to control intracellular messengers/ and regulate activity of cellular proteins
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4
Q

GPCR: structure/ function

A
  • all GPCRs have COMMON CORE (composed ofr 7 transmembrane helices) w/
    • *extracellular amino-terminal domain (N-terminal) and
    • intracellular C-terminal domain
    • TMs are connected by extracellular & intracellular loops
  • Receptors regulate ion channels via G proteins
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5
Q

G protein alpha subunits:

4 families

A

Gs

Gi

Gq

G12

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6
Q

Gs subunit:

function and members

A
  • Function: adenylyl cyclase activation
  • Members
    • G alpha s 1-4
    • G alpha olf
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7
Q

Gi/Go subunit:

function and members

A
  • Functions:
    • adenylyl cyclase INHIBITOR
    • K+ channel Activation
    • Ca2+ channel inhibition
    • PDE activation in rods, cones, tase epithelium
  • Members
    • G alpha I 1-3
    • G alpha O 1-2
    • G alpha T 1
    • G alpha GUST
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8
Q

Gq subunit:

functions and members

A
  • Function: PI-phospholipase C activation
  • Members:
    • Gq
    • G11, G14, G15, G16
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9
Q

G12 subunit:

function, members

A
  • Activation of RhoA thru RhoGEF; Regulate actin cytoskeleton remodeling
  • Function
    • G12, G13
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10
Q

describe the dual receptor regulation of adenylyl cyclase?

A
  • depending on the timing and receptors that are activated
  • Regulated by Rs and Ri
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11
Q

Formation and degradation of Cyclic AMP involves which steps?

A
  • Formation:
    • ATP –> [adenylyl cyclase] –> cyclic AMP
  • Degradation:
    • Cyclic AMP –>[phophodiesterase]; hydrolyzed by phosphodiesterase –> AMP
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12
Q

Purpose of Phospholipase C in the GPCR reactions?

A
  • GPCR activates phospholipase C (PLC)–>
    • PLC converts DAG –> IP3
      • DAG = diacylglycerol
      • IP3 = inositol 1,4,5 triphosphate
  • THEN
    • IP3 releases Calcium from intracellular storage sites
    • DAG activates protein kinase C in presence of Calcium
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13
Q

G beta-gamma Dimer:

  • function,*
  • examples*
A
  • interacts w/ diff’t effector molecules via protein-protein interactions
    • diff’t effectors are affected based on combination of Gbeta and Ggamma subunits
  • Examples:
    • regulates ion channels, such as G protein gated inward rectifier channels and calcium channels
    • Gbeta-gamma dimer activates or inhibits adenylyl cyclase
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14
Q

List the 7TMRs-1 families

A
  • adrenergic
  • dopamine
  • acetylcholine
  • GABA
  • serotonin
  • histamine
  • opioid
  • prostanoid
  • sensory
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15
Q

how many types of dopamine receptors are there? what about pharmacologically?

(effect?)

A
  • 5 dopamine receptors
  • ONLY 2 PHARMACOLOGICALLY
    • D1 –> Inc adenylyl cyclase
    • D2 –> Dec adenylyl cyclase
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16
Q

Ligand-gated ion receptors:

structure and function

A

Structure

  • made of 4-5 proteins –> form pore through membrane

Function:

  • Resting state: pore is CLOSED
  • When agonist binds (generally needs 2 molecules) –> pore opens –> depolarization/hyperpolarization of the postsynaptic cells
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17
Q

what are the ligand-gated ion channel receptors?

A
  • acetylcholine
  • adenosine triphosphate
  • glutamate
  • gamma-aminobutyric acid
  • glycine
  • 5-hydroxytrypamine
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18
Q

which receptors are pentameric complexes? (5 subunits)

A
  • Glycine and GABAa receptors
  • Nicotinic acetylcholine receptors
  • 5-HT3 serotonin receptor
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19
Q

Glycine and GABAa receptors:

structure, function and location

A
  • Structure: Pentameric complex
  • Fxn: Cl- channels, major INHIBITORY NT receptors in CNS;
  • Loc:
    • GABA in cortex/cerebellum
    • Glycine in spinal cord/brainstem
20
Q

Nictoninic acetylcholine receptors:

structure, fxn, agonists, location

A
  • Structure: Pentameric complex
    • Contain 2 alpha subunits –> affecting pharm
  • Fxn: Nicotinic acetylcholine receptors: cation selective
  • Agonists: nicotine and arecoline (alkaloid)
  • Location:
    • Primary excitatory receptor in skeletal muscles and peripheral NS, and CNS
21
Q

5-HT3 serotonin receptor:

structure, fxn, location

A
  • Structure: Pentameric complex receptor
  • Fxn: cation selective
  • Loc: exclusively on neurons
22
Q

What are the drugs that act on GABAa receptors?

A
  • Competitive: direct on GABA site –> bicuculline
  • Noncompetitive:
    • Benzodiazepine site - agonists
    • Barbiturate site - e.g. pentobarbital
    • Steroid site - anesthetics, anxiogenics
    • Picrotoxin - convulsants
23
Q

which receptors are Tetramer Ionotropic glutamate receptors?

& their functions

A
  • Members:
    • NMDA
    • AMPA
    • Kainate
  • Fxn
    • major excitatory NT receptors in CNS
    • play critical roles in synaptic plasticitiy (learning & memory)
24
Q

long term potentiation (LTP):

describe the process

A
  1. at resting membrane potentials, NMDA receptor pore is closed by Mg2+ / INACTIVE
  2. glutamate binds to AMPA receptor –> pore opens –> Na+ INFLUX –> depolarization
  3. depolarization –> repulsion of Mg2+ from NMDA receptor out into extracellular space –> allowing pore to pass both Na and Ca2+
  4. Ca2+ influx –> persistent modifications in strength of synaptic transmission
  5. results in increase in EPSP size –> LTP
25
Q

what major biochem outcome underlies Long-term potentiation?

A

long-lasting increase in EPSP size

26
Q

In addition to NMDA, AMPA receptors, which other receptors play a critical role in synaptic plasticity?

A

ionotropic glutamate plays a role in learning and memory

27
Q

NMDA receptor:

structure and antagonists

A
  • tetramer w/ pore; allows cations to pass thru
    • can form positive feedback look for LTP
  • antagonists: ketamine, phencyclidine
28
Q

Receptor tyrosine kinase:

fxn, classes, pathology, structure

A
  • fxn: when activated, assoc. w/ tyrosine kinase activity
    • involv. in growth/differentiation
      • regulate gene transcription
      • regulate phospholipase C-gamma
    • insulin receptor is involved in glucose regulation
  • ~20 diff’t RTK classes identified
    • Epidermal growth factor, Insulin, Nerve growth factor, Platelet derived growth factor, Macrophage-colony stimulating, Fibroblast growth factors,Vascular endothelial growth factor, Ephrin
  • path: mutations can lead to cancers
  • structure:
    • extracellular ligand-binding site
    • transmembrane core
    • tyrosine kinase intracellularly
29
Q

Effect of insulin on insulin receptors?

A
  1. binds to ligand-binding site –>
  2. changes conformation
  3. closes pore
  4. phosphate groups bind & translocate glucose transport protein into membrane
  5. glucose passes thru GLT protein (glucose transport protein) INTO cell
30
Q

Relationship w/ RTKs and cancer therapy?

A

small molecule inhibitors and monoclonal antibodies AGAINST receptor tyrosine kinases are used for cancer therapy

(typically end in -NIB or -MAB)

31
Q

which ligands act on the steroid hormone receptor family?

key characteristics?

A

derivatives of cholesterol! –> these penetrate cell membranes bc they’re highly lipophilic, –> carried by transport proteins in plasma

e.g.

  • glucocorticoids (mineralcorticoid aldosterone)
  • sex hormones (estrogens, progesterone, testosterone)
  • thyroid hormone (T3)
  • calcitriol (active form of D3)
  • Vit A and retinoic acid
32
Q

what is the state of steroid hormone receptors in ABSCENCE of ligand?

A

steroid hormone receptor maintains cytosolic inactive state by assoc. w/ heat shock proteins and/or other proteins (e.g. co-repressors)

thyroid hormone receptors are located in the nucleus (*NOT cytosol)

33
Q

what must a receptor do for a steroid hormone to regulate gene transcription?

A
  • BIND the hormone
  • steroid hormone receptor undergoes conformational changes –> released from repressor proteins
  • binds to second copy of itself to form homodimer
  • moves from cytosol to nucleus
  • binds to response element which is specific DNA sequence in the genes regulated by the hormone
34
Q

response element:

define, structure, regulation

A
  • def: part of the promoter of a gene
  • struc: DNA sequence bound by complex of ligand-steroid receptor
    • seq are specific for each hormone
  • fxn:
    • Steroid-receptor complex binding –> activate or repress the gene controlled by the response element
    • Mechanism can either turn on/off steroid hormones
35
Q

steroid hormone receptors:

define, fxn

A
  • ligand-activated transcription factors
  • fxn: regulate biological processes incl. metabolism, repro, and development
36
Q

Examples of drugs that act on Steroid Hormone Receptors?

A
  • Tamoxifen: selective estrogen receptor antagonist in breast tissue, used for tx of estrogen-dependent breast CA
  • Ethinyl estradiol, L-Norgestrel: acts on estrogen & progesterone receptors, respectively
    • both used in combined oral contraceptives
  • Thyroxine (T4): prodrug of tri-iodothyronine (T3), tx for hypothyroidism
37
Q

How is guanylyl cyclase regulated?

A

NOT BY GUANINE NUCLEOTIDE REGULATORY PROTEINS

Two mechanisms:

  • integral part of receptor and directly activated by ligand binding
    • (e.g. atrial natriuretic peptide)
  • cytoplasmic form which is activated by Nitric oxide
38
Q

second messengers:

function and examples

A
  • fxn: transduce the signal from membrane enzymes into intracellular events
  • eg. and major actions:
    • cyclic AMP –> activates protein kinase A
    • cyclic GMP –> activates protein kinase G
    • diacylglycerol –> activates protein kinase C
    • calcium –> activates Calmodulin-activated protein kinases
    • inositol triphosphate (releases Ca2+ –> inc calcium conc in the cytosol)
39
Q

processes between proteinand phosphorylated proteins?

A

protein KINASE adds phosphate

PHOSPHATASE removes phosphate

40
Q

which 3 amino acids can be phosphorylated?

A
  • SERINE
  • THREONINE
  • TYROSINE
41
Q

how can phosphorylation regulate enzymes and other proteins?

(list the various effects)

A
  • Lower Km or raise Vmax of enzymes
    • converseley, Raise Km or lower Vmax
  • Change affinity of enzyme for a protein cofactor
  • Alter rate of phosphorylation at another site
  • alter rate of protein degradation
  • alter protein-protein interactions
42
Q

how are second messengers removed?

A
  • phosphodiesterase acts on cyclic AMP and cyclic GMP
  • calcium - pumps to storage sites and to extracellular medium
  • diacylglycerol –> converted back to phosphatidyl inositol
    • IP3 is degraded by phosphatases
43
Q

examples of inhibitors of phosphodiesterase 5 (PDE5) for tx of erectile dysfunction?

A
  • Nitric Oxide (endothelium derived relaxation factor for smooth muscle)
    • NO activates soluble guanylyl cyclase –> converts GTP –> cGMP
    • cGMP vauses vasodilation –> [phosphodiesterse] –> GMP
  • PDE5 is located in corpus cavernosum and retina
  • Drugs: viagra, levitra, cialis –> selective inhibitors of PDE5
44
Q

Purpose of 7TMR regulation?

2 types? How do these differ

A
  • To prevent excessive response to a prolonged or overwhelming stimulus (e.g. smell)
  • Types
    • **Homologous
      • Receptor phosporylation –> uncoupled from G proteins
      • Receptor internalization into IC space
      • Receptor downregulated
    • Heterologous - various mechanisms
45
Q

agonist-induced internalization of 7TMR receptors:

define, & pathway

A

Define: rapid (minutes) agonist-induced internalization of the receptor into cell compartment distinct from plasma membrane, where it is UNAVAILABLE FOR SIGNAL TRANSDUCTION

  • important for reduced response and resensitization

Pathway:

  • agonist-promoted phosphorylation of receptor by GPCR kinases
  • binding of arrestins
  • binding of phosphorylated receptor-arrestin complex to adaptor proteins and clathrin
  • endocytosed by clathrin-coated vesicles in a dynamin-dependent manner
46
Q

downregulation of 7TMR receptors:

define, & pathway

A
  • more prolonged exposure –> reduction in # of receptors
  • enhanced receptor degradation
    • prolonged agonist stim –> GPCRs trafficked from endosomes –> lysosomes –> degraded by lysosomal enzymes
  • decreased receptor synthesis

Y1 - Pharm (12 decks)

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