4. Hormone Signaling Pathways Flashcards
Which subunit is the extracellular domain of tyrosine receptor kinase, and which is the intracellular domain?
The α subunit is extracellular, and of the β subunit is intracellular.
What are the second messengers for Gs, Gi, Gq, and Gt?
Gq: PLC/IP3.
Gs: ↑ adenylate cyclase.
Gi: ↓ adenylate cyclase.
Gt: cGMP phosphodiesterase.
What are the two phases of insulin secretion?
Why can’t both phases be released at the same time?
The “readily releasable pool (RRP).”
The “reserve pool.”
Granules in the reserve pool must undergo mobilization before they can gain release competence.
What is bound to cytoplasmic lipophilic hormone receptors before the hormone binds?
Heat shock protein 90 (HSP90).
What is the basic structure of insulin?
An A-chain connected to a B-chain by two disulfide bridges-with one disulfide bridge spanning a portion of the A-chain.
G proteins have their own GTPase to turn themselves off, but what enzyme can accelerate the inactivation of these G proteins by up regulating their intrinsic GTPase?
GTPase-activating protein (GAP) -> ↑ intrinsic GTPase
How does tamoxifen treat breast cancer?
Tamoxifen resembles estrogen, but after being metabolized by cytochrome P450 into 4-hydroxy-tamoxifen, attaches to the estrogen response element and recruits nuclear hormone receptor co-repressor, which promotes histone deacetylase activity (HDAC), which promotes tight binding of chromatin and inhibits transcription the cancer cells need to survive.
What are the three units of the trimeric G proteins?
α β γ
Where are estrogen receptor β’s (ERβ’s) most abundantly presented?
Ovaries.
Prostate.
Lower expression in lung, brain, bone, and vasculature.
What happens to the three subunits of a G-protein receptor when it becomes activated?
The α subunit dissociates from the β/γ subunits.
What is the effect of insulin on the number of insulin receptors?
Insulin down regulates its own receptor by decreasing rate of synthesis or increasing rate of degradation.
What transporter will glucose use to enter the beta cells of the pancreas?
GLUT2
What are the three domains of a receptor tyrosine kinase molecule?
An extracellular domain.
An α-helical transmembrane domain.
An intracellular domain with tyrosine kinase activity.
What are the three major types of lipophilic hormones?
Steroid hormones -progesterone, estradiol, testosterone, cortisol, aldosterone, vitamin D [1,25-dihydroxycholecalciferol].
Thyroid hormones - (thyroxine).
Retinoids - (retinol, retinoic acid).
How many times do G proteins cross the membrane?
G proteins are 7-transmembrane receptors!
(Apparently this is crazy high-yield)
Explain RAS-independent insulin signaling to the best of your ability.
In the case of RAS-independent insulin signaling, insulin binds to RTK which recruits insulin receptor substrate-1. This time IRS-1 recruits phosphoinositide-3-kinase (PI3kinase). PI3 kinase then phosphorylates phosphoinositides to form phosphatidylinositol 3,4-bisphosphate (PIP2) and phosphatidylinositol 3,4,5 trisphosphate (PIP3). PIP2 and PIP3 then activate second messengers to stimulate the recruitment of protein kinase B to the membrane, and activate it via phosphorylation. Downstream, this causes an increase in GLUT4’s movement to the plasma membrane, as well as activation of glycogen synthase. Ultimately both result in an increase in glucose uptake and glycogen synthesis.
Which estrogen receptor is thought to be the predominant form responsible for growth regulation of breast cancers?
Estrogen receptor α.
How do sulfonylurea drugs work?
They inhibit the ATP-sensitive K+ channel in the beta cells of the pancreas, causing depolarization of the membrane and calcium influx into the cell, encouraging release of insulin granules.
What five things, discussed in class, can lead to insulin resistance?
Down regulation of insulin receptor.
Defects in insulin signaling.
Defects in insulin receptor.
Defects in IRS 1 and IRS 2.
Serine/threonine kinase phosphorylating serine instead of tyrosine.
What are the two main receptors involving hydrophilic hormone signaling?
G-protein coupled receptors (GPCRs).
Receptor tyrosine kinases (RTKs).
What are some of the ways receptor tyrosine kinase signals are terminated?
Degradation of ligand by extracellular proteases.
Ligand induced endocytosis of receptor and its degradation.
RAS inactivation.
Dephosphorylation of protein targets by phosphatases.
Describe the process of nuclear receptor binding from before the ligand attaches, to the binding of the receptor to the hormone response element.
Before the ligand binds, the nuclear receptor is surrounded by inhibitory proteins.
After the ligand binds, the inhibitory proteins dissociate, the activation function domain (AF 1 / “transcription activating domain”) changes confirmation, and co-activator proteins bind.
The nuclear receptor complex then binds to the receptor binding element of the hormone response element and alters gene expression.
What is the basic pathway for the stimulation of insulin release in beta cells of the pancreas by glucose?
Glucose can enter the beta cells of the pancreas via GLUT2 (facilitated diffusion), glucokinase and become glucose 6-phosphate.
This glucose six phosphate travels through the TCA cycle and creates ↑ ATP.
This ATP causes the closing of an ATP-sensitive K+ channel, which causes an overall depolarization of the cell membrane.
This depolarization opens calcium channels, and the influx of calcium causes the release of insulin granules.
What happens when a receptor tyrosine kinase (RTK) receives a signal?
The intracellular tyrosine kinase domain becomes phosphorylated (and usually dimerizes), causing those phospho-tyrosines to be recognized by the adapter and docking proteins which activate downstream signaling pathways via RAS-dependent and RAS-independent pathways.
Either pathway results in phosphorylation of specific protein targets in the cytoplasm or nucleus.