Exam 2 (Lecture 14) Flashcards
Receptor Superfamilies
Nuclear Receptors Receptor Tyrosine Kinases (RTK) Cytokine Receptors Ligand-gated Ion Channel receptors G protein-coupled Receptors (GPCR)
Receptor Confirmations
2 Interconvertible confirmations
Active vs Inactive
Ligand doesn’t induce confirmation change, it locks its confirmation.
Nuclear receptors:
Physiological function and categorization
Ligands tend to be lipophilic
Regulate expression of specific genes
Participate in control of development, homeostasis and metabolism
Can directly bind DNA; classified as transcription factors
Receptors reside in either the cytoplasm or nucleus, in a complex with chaperone proteins (e.g., HSP90), and upon binding agonist the chaperones dissociate and receptors DIMERIZE either with themselves (homodimers) or another nuclear receptor (heterodimers).
Receptor dimers bind to specific sites on DNA (promoter regions) designated as HREs with palindromic sequences (e.g. ATTCGGCTTA) which bind dimeric receptors and facilitate binding of other transcription factors
HRE
Hormone-responsive elements
Steroid receptors
Estrogen Androgen Glucocorticoid (cortisol) Mineralcorticoid (aldosterone) Vitamind D
Representative Therapeutics
Enzalutamide - prostate cancer
Tamoxifen - breast cancer
Lipaglyn - type II diabetes
Cortisone - anti-itch and pain relief
glucocorticoids
controls metabolism and decrease inflammation
used to treat allergies, asthma, autoimmune diseases, sepsis; lymphomas and leukemias
BDNF
Pain and neuronal disease
GDNF
Gene therapy for Parkinson’s disease
Infliximab
antibody that neutralizes TNF alpha and treats Crohn’s disease
Etanercept
fusion protein that works as TNF alpha inhibitor and treats arthritis
STAT protein
binds to sites called GAS (Gamma-activated-sites) in the promoter region of cytokine inducible genes and activates transcription
nuclear phosphatases can inactivate
Natural ligands
acetylcholine, serotonin, GABA, glutamate
Pentameric cys-loop cationic receptors ( 5 subunits)
5-HT, nicotinic acetylcholine
Pentameric cys-loop anionic receptors (5 subunits)
GABAA, Glycine
Ionotropic glutamate receptors (cation, 4 subunits)
AMPA, Kainate, NMDA
P2X purinoreceptors (cation)
3 subunits
Benzodiazepines
positive allosteric modulators, enhance effect of GABA at GABAa receptor
Barbiturates
Same effects as benzodiazepine but more toxic so been replaced
Classes of G proteins
GTPi, GTPq,GTPs, GTP12
GTPi
Inhibition of cAMP production, ion channels, phosphodiesterase, phospholipases
GTPq
increase IP3 -> increase CA2+
Increase DAG -> increase Protein Kinase C
GTPs
increase in cAMP concentration
GTP12/13
RhoGEF -> RhoA -> ROCK
Gs vs Gi effects
Gi and Gs regulate the Adenylate Cyclase/cAMP/PKA signaling pathway
Norepinephrine (alpha receptor) inhibit pathway(Gi)
Epinephrine (beta receptor) active pathway (Gs)
alpha receptor = gi
beta receptor = gs
Gq pathway
Gq -> PLC -> PIP2 -> IP3 -> Ca2+ -> Calmodulin Binding enzymes
Gq -> PLC -> DAG -> PKC -> Kinase cascade
G protein activation cycle
Agonist activates the receptor, which promotes the release of GDP from the G protein.
This allows entry of GTP into the nucleotide binding site.
In its bounds state, the G protein regulates activity of an effector enzyme or ion channel.
Signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state.
Rapid desensitization
Exposure of cells to agonist produces cAMP response.
reduced response observed in continued presence of agonist (desensitization) occurs in a few minutes.
If agonist is removed after short time, cells can recover to full responsiveness to another addition of agonist (resensitization)
This resensitization fails to occur, or occurs incompletely if cells are exposed to agonist repeatedly or over a more prolonged time period.
Re
Down regulation of B adrenoreceptors
- Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins in cytoplasm
- Agonost-activated proteins are phosphorylated by GRK, preventing interaction with Gs and promoting binding of B-arrestin.
- Receptor-arresting complex binds to coated pits, promoting internalization.
- Agonist dissociates from internalized receptor, Redding affinity for B-arrestin and allows for dephospho rylation by P’ase and return receptor to membrane. This is resensitization.
- repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes, promoting down-regulation instead of resensitization.
Key Steps in Signal Transduction
- release of primary messenger, GPCR ligand
- reception of primary messenger, signal molecule binds to receptor
- relay: modulation by other factors
- Amplification
- Delivery of the message inside the cell by 2nd messenger to multiple targets.
Second messangers
cGMP, cAMP, IP3, DAG, calcium, Nitrix Oxide (NO)
Signal can be amplified,
can be stored in organelles
Common second messengers may create “cross talk”
cAMP downstream resposne
Once cAMP is made, it binds to Protein Kinase A
C subunit gets released and goes into nuclease, activates transcription factor (CREB)
Plays a role in memory and learning
Inhibition Mechanism for downstream response
Phosphatases: Takes away phosphorylation (dephosphorylation)
Phosphodiesterase (PDE): inhibitor for cAMP
Interactions with other receptors
GPCR can directly (via G protein) or indirectly (via second messenger) gate ion channels
RTKs can also gate ion channels
Class A vs Class C G-protein receptors
Class A: for Neuropharmacology do not dimerize
Class C: dimerize
