4 - Receptors Flashcards
(46 cards)
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
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
3
Q
GPCR aka Seven-transmembrane receptors (7TMRs);
G-protein cycle
A
- GPCR receives an extracellular stimulus (e.g. light, calcium, odorants, pheromones)
- 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)
- G-protein heterotrimeric complex then interacts w/ diverse group of effectors to control intracellular messengers/ and regulate activity of cellular proteins
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
5
Q
G protein alpha subunits:
4 families
A
Gs
Gi
Gq
G12
6
Q
Gs subunit:
function and members
A
- Function: adenylyl cyclase activation
- Members
- G alpha s 1-4
- G alpha olf
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
8
Q
Gq subunit:
functions and members
A
- Function: PI-phospholipase C activation
- Members:
- Gq
- G11, G14, G15, G16
9
Q
G12 subunit:
function, members
A
- Activation of RhoA thru RhoGEF; Regulate actin cytoskeleton remodeling
- Function
- G12, G13
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
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
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
- PLC converts DAG –> IP3
- THEN
- IP3 releases Calcium from intracellular storage sites
- DAG activates protein kinase C in presence of Calcium
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
14
Q
List the 7TMRs-1 families
A
- adrenergic
- dopamine
- acetylcholine
- GABA
- serotonin
- histamine
- opioid
- prostanoid
- sensory
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
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
17
Q
what are the ligand-gated ion channel receptors?
A
- acetylcholine
- adenosine triphosphate
- glutamate
- gamma-aminobutyric acid
- glycine
- 5-hydroxytrypamine
18
Q
which receptors are pentameric complexes? (5 subunits)
A
- Glycine and GABAa receptors
- Nicotinic acetylcholine receptors
- 5-HT3 serotonin receptor
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
- at resting membrane potentials, NMDA receptor pore is closed by Mg2+ / INACTIVE
- glutamate binds to AMPA receptor –> pore opens –> Na+ INFLUX –> depolarization
- depolarization –> repulsion of Mg2+ from NMDA receptor out into extracellular space –> allowing pore to pass both Na and Ca2+
- Ca2+ influx –> persistent modifications in strength of synaptic transmission
- results in increase in EPSP size –> LTP
25
what major biochem outcome underlies Long-term potentiation?
long-lasting increase in EPSP size
26
In addition to NMDA, AMPA receptors, which other receptors play a critical role in synaptic plasticity?
ionotropic glutamate plays a role in learning and memory
27
NMDA receptor:
## Footnote
*structure and antagonists*
* tetramer w/ pore; allows cations to pass thru
* can form positive feedback look for LTP
* antagonists: ketamine, phencyclidine
28
Receptor tyrosine kinase:
## Footnote
*fxn, classes, pathology, structure*
* 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
Effect of insulin on insulin receptors?
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
Relationship w/ RTKs and cancer therapy?
small molecule inhibitors and monoclonal antibodies AGAINST receptor tyrosine kinases are used for cancer therapy
(typically end in -NIB or -MAB)
31
which ligands act on the **steroid hormone receptor** family?
key characteristics?
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
what is the state of steroid hormone receptors in ABSCENCE of ligand?
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
what must a receptor do for a steroid hormone to regulate gene transcription?
* 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
response element:
## Footnote
*define, structure, regulation*
* 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
steroid hormone receptors:
## Footnote
*define, fxn*
* ligand-activated **transcription factors**
* fxn: regulate biological processes incl. metabolism, repro, and development
36
Examples of drugs that act on Steroid Hormone Receptors?
* **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
How is guanylyl cyclase regulated?
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
second messengers:
## Footnote
*function and examples*
* 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
processes between proteinand phosphorylated proteins?
protein KINASE adds phosphate
PHOSPHATASE removes phosphate
40
which 3 amino acids can be phosphorylated?
* SERINE
* THREONINE
* TYROSINE
41
how can phosphorylation regulate enzymes and other proteins?
(list the various effects)
* 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
how are second messengers removed?
* **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
examples of **inhibitors of phosphodiesterase 5 (PDE5)** for tx of erectile dysfunction?
* 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
Purpose of 7TMR regulation?
2 types? How do these differ
* 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
**agonist-induced internalization** of 7TMR receptors:
*define*, *& pathway*
# 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
**downregulation** of 7TMR receptors:
## Footnote
*define, & pathway*
* 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
