2-1-16-Hormone Signaling Pathways (Zaidi) Flashcards
What type of receptors are involved in hydrophilic hormone signaling?
GPCRs
RTKs
Regarding cytoplasmic receptors, the hormone-receptor complex translocates to the nucleus where it binds to specific DNA sequence called the ___ in the promoter region of specific genes
Hormone Response ELement
Steroid hormones are ___ molecules
Epinephrine and insulin are ___ molecules
Use either hydrophobic or hydrophilic
Hydrophobic
Hydrophilic
___ medications have short 1/2 lives, i.e., epinephrine is contained in autoinjectors used to treat severe acute allergic rxns that may lead to anaphylactic shock. Given at time of need
___ meds have long 1/2 lives, i.e., oral contraceptives contain ethinyl estradiol, a derivative of estradiol. Need to take daily
Hydrophilic
Lipophilic
An inactive G protein has GDP bound to its alpha subunit, which is attached to the beta and gamma subunits. To become active, the G protein must exchange its GDP for GTP which occurs via the action of a ____
Guanine nucleotide exchange factor (GEF)
To return active GTP to its inactive GDP, the intrinsic GTPase activity of the protein hydrolyzes its bound GTP to GDP and Pi and is accelerated by ____
GTPase-activating protein (GAP)
___ stimulates AC
___ inhibits AC
___ stimulates hydrolysis of cGMP
Gs
Gi
Gt
GPCR signaling via Gq leads to downstream activation of:
GTP-alpha activating PLC –> PIP 2 —> IP3 and DAG –> IP3 binds Ca channels and releases sequestered ER/SR Ca which then can bind with calmodulin and activate Ca-calmodulin dependent proteins or activate PKC which phosphorylates target proteins to alter their activities –> DAG can activate PKC directly
What are the effects of Epi binding to Gs protein and B-adrenergic receptor?
Relaxation of bronchial and intestinal smooth m., contraction of heart muscle, increased breakdown of TAGs in adipose, increase breakdwon of glycogen in liver and muscle, increased glycolysis in muscle.
Epi is a non-selective agonist of all adrenergic receptors and undergoes multipled GPCR signaling pathways
What are the effects of histamine binding to a Gs histamine H2 receptor?
Bronchoconstriction and symptoms of allergic rxns
What are effects of epi/norepi binding to a Gi alpha-adrenergic receptor?
constriction of smooth m.
Inactive insulin is stored in the body as a ___, while the active form is the ___
Insulin has a 3-fold symmetry with ___ in the center connected to the polypeptide via histidines
Hexamer
Monomer
Zinc
Insulin signaling occurs through ___
Ras-dependent and indepent Receptor Tyrosine Kinase
Describe insulin signaling through Ras-dependent pathway
Insulin bind insulin RTK –> IRS-1 binds GRB-2 –> Ras –> Phosphorylated protein –> Alteration in gene transcription, e.g., increased transcription of glucokinase –> increase glucose uptake and/or glycogen synthesis
Describe insulin signaling through RAS-independent pathway:
Insulin binds insulin RTK –> IRS-1 binds PI-3 kinase –> PKB –> Phosphorylated protein –> alterations in protein and enzyme activity e.g., increased GLUT4 movement to plasma membrane; activation of glycogen synthase –> increase glucose uptake and/or glycogen synthesis
Under ___ conditions, insulin lowers blood glucose by promoting glycogen synthesis, stimulating glycolysis, and inhibiting the activity and synthesis of enzymes for gluconeogenesis
Fed
List classic steroid nuclear receptors:
The ligands are lipophilic hormones
Glucocorticoids (GR) Mineralocorticoids (MR) Estrogen (ER) Progesterone (PR) Androgens (AR)
List orphan receptors/their ligands:
Retinoids Thyroid Vitamin D Xenobiotics Androstane
What are the 3 major domains of nuclear receptors?
AF1
DBD
LBD
___ domain is independent of ligand binding, can modify the conformation of the entire receptor
AF1 (Activation Function 1 domain)
___ domain is highly conserved, binds to regulatory sequences on DNA called HRE, upstream of target gene
DBD (DNA binding domain)
___ domain binds to various molecules (agonist or antagonist) which regulates ligand-dependent activation of receptor. Upon ligand binding a region within this domain, it undergoes conformational changes allowing recruitment and binding of coactivators or corepressors that regulate transcription
LBD (ligand binding domain)
___ is expressed most abundantly in the female reproductive tract (especially in the uterus, vagina, and ovaries). Also in the mammary gland, hypothalamus, endothelial cells, and vascular smooth m.
ER-alpha
___ is expressed most abundantly in the prostate and ovaries, with lower expression in lung, brain, bone, and vasculature
ER-beta
Both ERalpha and beta are expressed in ___, although ERalpha is believed to be the predominant form responsible for growth regulation
Breast cancers
One of the critical aspects of insulin resistance leading to diabetes is a loss of insulin stimulation of glucose uptake by ___ in adipose and skeletal muscle.
GLUT4
When glucose deficiency occurs (starved), the pancreas releases the peptide hormone ____. Similarly, ___ stimulates the breakdown of glycogen by promoting glucagon secretion. If the glycogen stores have been depleted, then the steroid hormone ___ stimulates gluconeogenesis by inducing transcription of enzymes involved in glucose-producing pathway.
Glucagon
Epinephrine
Cortisol
List examples of hydrophilic hormones:
Epi, insulin, glucagon
____ is an drug that acts as an antagonist to estrogen and binds to Estrogen receptor but produces a different receptor conformation
Tamoxifen –> different set of proteins called co-repressors, such as NcoR, are recruited to the complex. NcoR further recruits proteins such as HDAC1 that act on histone proteins to stabilize the nucleosome structure and prevent interaction with the GTA
