4 - Receptors Flashcards
four major types of receptors?
G - TLC
- G-protein-coupled receptors (GPCRs), aka seven transmembrane receptors (7-TMRs)
- receptor Tyrosine kinase
- Ligand-gated ion channels
- Cytosolic receptors
GPCR aka Seven-transmembrane receptors (7TMRs);
- type/quantity,*
- purpose in pharm*
- ~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
GPCR aka Seven-transmembrane receptors (7TMRs);
G-protein cycle
- 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
GPCR: structure/ function
- 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
G protein alpha subunits:
4 families
Gs
Gi
Gq
G12
Gs subunit:
function and members
- Function: adenylyl cyclase activation
- Members
- G alpha s 1-4
- G alpha olf
Gi/Go subunit:
function and members
- 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
Gq subunit:
functions and members
- Function: PI-phospholipase C activation
- Members:
- Gq
- G11, G14, G15, G16
G12 subunit:
function, members
- Activation of RhoA thru RhoGEF; Regulate actin cytoskeleton remodeling
- Function
- G12, G13
describe the dual receptor regulation of adenylyl cyclase?
- depending on the timing and receptors that are activated
- Regulated by Rs and Ri
Formation and degradation of Cyclic AMP involves which steps?
- Formation:
- ATP –> [adenylyl cyclase] –> cyclic AMP
- Degradation:
- Cyclic AMP –>[phophodiesterase]; hydrolyzed by phosphodiesterase –> AMP
Purpose of Phospholipase C in the GPCR reactions?
- 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
G beta-gamma Dimer:
- function,*
- examples*
- 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
List the 7TMRs-1 families
- adrenergic
- dopamine
- acetylcholine
- GABA
- serotonin
- histamine
- opioid
- prostanoid
- sensory
how many types of dopamine receptors are there? what about pharmacologically?
(effect?)
- 5 dopamine receptors
- ONLY 2 PHARMACOLOGICALLY
- D1 –> Inc adenylyl cyclase
- D2 –> Dec adenylyl cyclase
Ligand-gated ion receptors:
structure and function
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
what are the ligand-gated ion channel receptors?
- acetylcholine
- adenosine triphosphate
- glutamate
- gamma-aminobutyric acid
- glycine
- 5-hydroxytrypamine
which receptors are pentameric complexes? (5 subunits)
- Glycine and GABAa receptors
- Nicotinic acetylcholine receptors
- 5-HT3 serotonin receptor
Glycine and GABAa receptors:
structure, function and location
- Structure: Pentameric complex
- Fxn: Cl- channels, major INHIBITORY NT receptors in CNS;
- Loc:
- GABA in cortex/cerebellum
- Glycine in spinal cord/brainstem
Nictoninic acetylcholine receptors:
structure, fxn, agonists, location
- 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
5-HT3 serotonin receptor:
structure, fxn, location
- Structure: Pentameric complex receptor
- Fxn: cation selective
- Loc: exclusively on neurons
What are the drugs that act on GABAa receptors?
- Competitive: direct on GABA site –> bicuculline
- Noncompetitive:
- Benzodiazepine site - agonists
- Barbiturate site - e.g. pentobarbital
- Steroid site - anesthetics, anxiogenics
- Picrotoxin - convulsants
which receptors are Tetramer Ionotropic glutamate receptors?
& their functions
- Members:
- NMDA
- AMPA
- Kainate
- Fxn
- major excitatory NT receptors in CNS
- play critical roles in synaptic plasticitiy (learning & memory)
long term potentiation (LTP):
describe the process
- 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
what major biochem outcome underlies Long-term potentiation?
long-lasting increase in EPSP size
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
NMDA receptor:
structure and antagonists
- tetramer w/ pore; allows cations to pass thru
- can form positive feedback look for LTP
- antagonists: ketamine, phencyclidine
Receptor tyrosine kinase:
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
- involv. in growth/differentiation
- ~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
Effect of insulin on insulin receptors?
- binds to ligand-binding site –>
- changes conformation
- closes pore
- phosphate groups bind & translocate glucose transport protein into membrane
- glucose passes thru GLT protein (glucose transport protein) INTO cell
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)
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
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)
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
response element:
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
steroid hormone receptors:
define, fxn
- ligand-activated transcription factors
- fxn: regulate biological processes incl. metabolism, repro, and development
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
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
second messengers:
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)
processes between proteinand phosphorylated proteins?
protein KINASE adds phosphate
PHOSPHATASE removes phosphate
which 3 amino acids can be phosphorylated?
- SERINE
- THREONINE
- TYROSINE
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
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
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
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
- **Homologous
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
downregulation of 7TMR receptors:
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
