Hormone Signaling Pathways Flashcards by Sarah Gillen

Hormones are messenger molecules synthesized and secreted by _______ cells. They are released into ______ or the blood stream and exert their influence by binding receptors on cells of remote target tissues

Endocrine

ECF

How well did you know this?

Not at all

Perfectly

Hormones binding their receptors results in activation of signal ______ and/or alteration in ______ expression ultimately leading to cell type-specific response

Only a small amount is required to alter cell metabolism because the effect is greatly magnified via signal ________

Transduction; gene

Amplification

How well did you know this?

Not at all

Perfectly

Multistep process of hormone signaling

Biosynthesis
Storage
Secretion
Transport to target tissue/cells
Recognition and binding to receptors
Activation of signal transduction pathway
Amplification and relay of signal
Cellular response
Degradation

How well did you know this?

Not at all

Perfectly

4 types of cell signaling

Endocrine
Paracrine
Autocrine
Juxtacrine

How well did you know this?

Not at all

Perfectly

___________ signaling = signaling molecule released by a cell distant from target cell and transported via blood to target cell

Endocrine

How well did you know this?

Not at all

Perfectly

___________ signaling = signaling molecule acts on same cell type as secreting cell itself (ex. IL-1)

Autocrine

How well did you know this?

Not at all

Perfectly

___________ signaling = signaling molecule released by one cell type and diffuses to neighboring target cell of a different type

Paracrine

How well did you know this?

Not at all

Perfectly

___________ signaling = signaling molecule stays attached to secreting cell and binds receptor on adjacent target cell via connexons (ex. Heparin-binding epidermal growth factor)

Juxtacrine

How well did you know this?

Not at all

Perfectly

T/f: some signaling molecules participate in more than one type of signaling

True

How well did you know this?

Not at all

Perfectly

Which of the following is typical of testosterone?

A. Endocrine signaling
B. Paracrine signaling
C. Autocrine signaling
D. Juxtacrine signaling

B. Paracrine signaling

How well did you know this?

Not at all

Perfectly

Which of the following is typical of epinephrine?

A. Endocrine signaling
B. Paracrine signaling
C. Autocrine signaling
D. Juxtacrine signaling

A. Endocrine signaling

How well did you know this?

Not at all

Perfectly

Which of the following are hydrophilic hormones?

A. Epinephrine
B. Insulin
C. Steroid hormones
D. Glucagon
E. Thyroid hormone
F. Retinoids

A. Epinephrine
B. Insulin
D. Glucagon

How well did you know this?

Not at all

Perfectly

Which of the following are lipophilic hormones?

A. Epinephrine
B. Insulin
C. Steroid hormones
D. Glucagon
E. Thyroid hormone
F. Retinoids

C. Steroid hormones
E. Thyroid hormones
F. Retinoids

How well did you know this?

Not at all

Perfectly

What types of receptors are involved in hydrophilic hormone signaling?

GPCRs

RTKs

How well did you know this?

Not at all

Perfectly

Lipophilic hormones pass through the plasma membrane of the target cell and bind to either ______ receptors or ______ receptors, either way regulating the transcription of specific genes

Cytoplasmic

Nuclear

How well did you know this?

Not at all

Perfectly

Describe lipophilic hormone signaling via cytoplasmic receptors

They exist in an inactive complex with HSP90. Upon binding to signal, the HSP dissociates

The hormone receptor complex translocates to nucleus where it binds to a specific DNA sequence called the hormone response element (HRE) in the promoter region of specific genes

How well did you know this?

Not at all

Perfectly

Describe lipophilic hormone signaling via nuclear receptors

They are already present in the nucleus bound to DNA. The hormone signal activates the complex and allows for interactions with additional proteins

How well did you know this?

Not at all

Perfectly

Epinephrine is a ______ signal that binds a _______ to cause cellular response

Hydrophilic; GPCR

How well did you know this?

Not at all

Perfectly

Insulin is a ______ signal that binds a _______ to cause cellular response

Hydrophilic; RTK

How well did you know this?

Not at all

Perfectly

What is the difference between lipophilic and hydrophilic medications?

Hydrophilic have SHORT half lives (e.g. epinephrine); given at time of need

Lipophilic have long half lives (e.g. oral contraceptives); taken daily

How well did you know this?

Not at all

Perfectly

GPCR signaling occurs via trimeric G proteins containing 3 subunits (_____, _____, ____)

An inactive G protein has GDP bound to its _____ subunit, which is attached to the other 2 subunits.

To become active, the G protein must exchange its GDP for a GTP, this occurs via the action of _______

The active GTP-bound ____ subunit separates from the other 2 to potentiate activation signal

Alpha, beta, gamma

Alpha

GEF (guanine nucleotide exchange factor)

Alpha

How well did you know this?

Not at all

Perfectly

For a GPCR to return to its inactive state, the intrinsic GTPase activity of the G protein hydrolyzes its bound GTP to GDP and Pi

This action is accelerated by a ______

GAP (GTPase-activating protein)

How well did you know this?

Not at all

Perfectly

Describe 4 different GPCR signaling variations: Gs, Gt, Gi, Gq

Gs = stimulates adenylate cyclase, forms cAMP, activates PKA, phosphorylates targets

Gt = stimulates hydrolysis of cGMP by phosphodiesterase

Gi = inhibits adenylate cyclase

Gq = stimulates PLC —> DAG and IP3 —> PKC and calcium/calmodulin

How well did you know this?

Not at all

Perfectly

Epinephrine binds beta-adrenergic GPCR, activating _____ subunit

What is the physiologic response?

Relaxation of bronchial and intestinal smooth muscle, contraction of heart muscle, increased breakdown of TAGs in adipose tissue, increased breakdown of glycogen in liver and muscle, increased glycolysis in muscle

[epinephrine is a non-selective agonist of all adrenergic receptors and results in multpile GPCR signaling pathways]

How well did you know this?

Not at all

Perfectly

Histamine binds ______ GPCR, activating _____ subunit What is the physiologic response?

Histamine H2; Gs Bronchoconstriction and symptoms of allergic reaction (e.g. itchy, watery eyes)

Epinephrine/Norepinephrine binds alpha-adrenergic GPCR, activating _____ subunit What is the physiologic response?

Gi Constriction of smooth muscle

Dopamine binds ______ GPCR, activating _____ subunit What is the physiologic response?

Dopamine D2; Gi Increased heart rate

Acetylcholine binds ______ GPCR, activating _____ subunit What is the physiologic response?

Muscarinic ACh M3; Gq Bronchoconstriction and stimulation of salivary glands

Light binds ______ GPCR, activating _____ subunit What is the physiologic response?

Rhodopsin; Gt Vision

RTKs have an extracellular domain that binds the ligand/signaling molecule, a single ________ transmembrane domain, and an intracellular domain with _____ activity

Alpha-helical; tyrosine-kinase

Typical ligands of RTKs are growth factors. What is the result of ligand binding to RTK extracellular domain?

Dimerization The dimerized receptor then phosphorylates tyrosine residues

Dimerized RTKs phosphorylate tyrosine residues. What effect does this have on signaling process?

Phosphotyrosines are recognized by adaptor and docking proteins which activate downstream signaling pathways (RAS dependent and RAS independent) - both of which trigger phosphorylation of specific protein targets in cytoplasm/nucleus leading to alterations in gene transcription and protein activity

Are MAPK pathway signals RAS-dependent or RAS-independent?

RAS-dependent [RAS-independent include other kinases]

How is RTK signaling terminated?

Multiple mechanisms: degradation of ligand by EC proteases, ligand-induced endocytosis of receptor and its degradation, RAS inactivation, dephosphorylation of protein targets by phosphatases

Primary structure of insulin

2 peptide chains: A chain and B chain, linked together by 2 disulfide bridges, and an additional disulfide is formed within the A chain

In most species the A chain of insulin consists of ____ amino acids and the B chain of ____ amino acids

21; 30

The secondary and tertiary structure of insulin involves 6 insulin molecules assembled in a ______ with 3-fold symmetry with _____ in the center, connected to the polypeptide via ________

Hexamer; zinc; histidines

Inactive insulin is stored in the body as a ______, while the active form is the _____

Hexamer; monomer

Insulin synthesis and secretion: Glucose upregulates ______ mRNA, which is translated into ______ protein. This gets translocated into _____ lumen

Preproinsulin; preproinsulin; ER

Describe insulin synthesis and secretion once the preproinsulin protein has been translocated to the ER lumen

It is cleaved by a protease to form proinsulin, folded and transported to golgi, packaged into clathrin coated granules, cleaved by proteases to form insulin and C peptide, forms mature granules containing hexameric crystallized insulin (3dimers), insulin + C peptide released together by beta cells of pancreas

After glucose stimulation, insulin is released in what 2 distinct phases?

First phase = rapid but transient; comes from limited pool of granules referred to as readily releasable pool (RRP) - <5% Second phase = sustained; comes from larger pool referred to as reserve pool. Granules in this pool must undergo mobilization before they can gain release competence - >95%

Regulation of insulin synthesis and secretion: Glucose binds ______ receptor, resulting in _______ enzyme forming G1P Insulin granules are released by opening of ______ channels in cell membrane, as well as closing of ATP-sensitive _____ channels when energy in cell increases

GLUT2; glucokinase Ca++; K+

Describe Ras-dependent insulin signaling

Insulin binds to RTK which exists as preformed dimer, causing autophosphorylation of tyrosine residues Phosphotyrosine residues are recognized and bound by IRS-1, which is phosphorylated on its tyrosine by insulin receptor Phosphorylated IRS-1 is recognized and bound by adaptor protein GRB-2, initiating activation of Ras and Map kinase pathway Results in phosphorylation of nuclear proteins that increase transcription of glucokinase Glucokinase phosphorylates glucose in the first step of glycolysis and glycogen synthesis

Describe Ras-independent insulin signaling

Insulin binds RTK which exists as a preformed dimer, causing autophosphorylation of the tyrosin residues Phosphotyrosine residues recognized and bound by IRS-1 IRS-1 phosphorylated on its tyrosin by insulin receptor Phosphorylated IRS-1 recruits PI3kinase, which phosphorylates phosphoinositides to form PIP3 PIP3 act as second messengers, stimulating recruitment of PKB to the membrane and its activation by phosphorylation Active PKB (serine threonine kinase aka Akt) phosphorylates and alters IC proteins to stimulate glucose uptake and storage (upregulates GLUT4, inhibits glycogen synthase kinase via phosphorylation)

What quantifiable lab parameter is measured as the amount of glucose cleared from the blood in response to a fixed dose of insulin?

Insulin resistance

What types of conditions might lead to insulin resistance?

Defects in insulin signaling (receptor activation to translocation of GLUT4) Mutations in insulin receptor Increased phosphorylation of serine (via ser/thr kinase) instead of tyrosine in IR and IRS - inhibits activation and signaling

Insulin resistance may result d/t increased phosphorylation of serine via ser/thr kinase instead of tyrosine in the IR and IRS - which inhibits activation and signaling Phosphorylation of IRS is needed for recruitment of PI3 kinase but ser/thr phosphorylation appears to inactivate the IRS 1 and 2, leading to degradation What activates the Ser/Thr kinase to cause this effect?

``` Cytokines Free fatty acids DAG Ceramide Inflammatory molecules ```

What hormone is released from the pancreas under conditions of hunger

Glucagon

How does glucagon increase blood sugar

Promoting breakdown of glycogen in liver and inhibiting glycogen synthesis

How does epinephrine affect glycogen breakdown

Stimulates it by promoting glucagon secretion

Upon depletion of glycogen stores, the steroid hormone _____ stimulates gluconeogenesis by inducing transcription of enzymes involved in this path

Cortisol

Nuclear receptors are a large family of receptors classified based on ligands they bind. What are the 3 general classifications?

Classic NRs - ligands are lipophilic hormones like glucocorticoids, mineralocorticoids, estrogen, progesterone, androgens Orphan NRs - other group of receptors discovered by DNA sequencing (ligands unknown) Adopted NRs - orphan NRs whose ligands have been discovered like retinoids, thyroid hormones, vitamin D, xenobiotics, androstane, etc.

NRs may be localized in what 2 locations

Nucleus | Cytosol

What are some diseases involving abberrations in NR signaling?

``` Reproductive disorders Cancer Diabetes Inflammation Cardiovascular disorders Obesity ```

NRs share the same architecture What are the 3 major domains?

Activation 1 domain (AF1) DNA binding domain (DBD) Ligand binding domain (LBD)

Describe the activation function 1 domain (AF1) of NRs

Independent of ligand binding, can modify the conformation of entire receptor

Describe the DND binding domain (DBD) of NRs

Highly conserved; binds regulatory sequences on DNA called hormone response element (HRE), upstream of target gene

Describe Ligand Binding domain (LBD) of NRs

Binds various molecules (agonist or antagonist) which regulates ligand-dependent activation of the receptor Upon ligand binding within LBD, conformational changes occur allowing recruitment and binding of coactivators or corepressors that regulate transcription

T/F: NRs exist as homo or heterodimers

True

2 major types of estrogen receptor

ER-alpha ER-beta

The 2 major types of estrogen receptors, ER-alpha and beta, are products of 2 separate genes located on different chromosomes Their structure is the almost the same with some differences. Both are estrogen-dependent ________ ________

Transcription factors

ER-alpha was the first estrogen receptor discovered. Where is it most abundantly expressed?

Female reproductive tract (uterus, vagina, ovaries) Mammary gland, hypothalamus, endothelial cells, vascular smooth muscle

Where is ER-beta most abundantly expressed?

Prostate and ovaries Lower expression in lung, brain, bone, vasculature

T/F: Many cells express both ER-alpha and beta They dimerize to form either homo or heterodimers, and the final biological effect is mediated by the ratio of the 2 forms

True

Both ER-alpha and beta are expressed in breast cancers, although _____ is believed to be the predominant form responsible for growth regulation

ER-alpha

Estrogen acts as an _______ at the ER, upregulating ______activity and ______ transcription

Agonist HAT Activating

Tamoxifen acts as an _______ at the ER. It is first converted to 4-hydroxy-tamoxifen via _______ metabolism, which then upregulates _____ activity and ______ transcription

Antagonist CytP450 HDAC Inhibist

Molecular MOA of nuclear estrogen receptor: ER exists as a _____ within the nucleus The ligand binds the receptor, causing conformational change facilitating _________ with specific estrogen response element sequences in DNA The ER-DNA complex recruits _______ that modify chromatin structure and SRC-1, which further alters chromatin structure by virtue of its _______ activity Chromatin remodeling facilitates binding of other coactivators to promoter of target genes and recruit proteins that comprise the general _______ apparatus, leading to enhanced transcription to form mRNA

Monomer Dimerization Co-activators; HAT Transcription

T/F; Although it is thought that ER exists as a monomer within the nucleus, some evidence suggests it can be located in the cytosol and estrogen binding causes dimerization and translocation to the nucleus

True

Antagonists like tamoxifen recruit HDACs which act on histone proteins to stabilize nucleosome structure; how do things like tamoxifen prevent transcription?

By stabilizing the nucleosome structure, they prevent interaction with the general transcription apparatus and prevent transcription

Some ERs are considered non-genomic, where are their receptors located and what type of receptors are they?

Some in PM Some in caveolae (cholesterol enriched domains in PM) There are GPCR and RTK type non-genomic ERs

How are non-genomic ER effects mediated?

Through metabolic changes as well as changes in gene expression

Production of gonadal hormones testosterone and estrogen are under the control of the ______ and _______

Hypothalamus; anterior pituitary

Cortisol, aldosterone, and androgens are steroid hormones synthesized in the ________

Adrenal cortex

Estrogens and progesterone are steroid hormones synthesized in _____

Ovaries

What steroid hormone is synthesized in the placenta?

Progesterone

Is histamine lipophilic or hydrophilic? What type of receptor does it bind?

Hydrophilic Binds GPCR

Differentiate type I vs. type II nuclear receptors

Type I - reside in cytoplasm with ligand-mediated translocation to the nucleus Type II - reside in nucleus to mediate active repression of gene expression until hormone binding comes in to change the response

Estrogen receptors bind to core inverted repeat DNA sequences using 2 _________ that are ________

Zinc-fingers; palindromes

What happens to the co-activators or co-repressors when a hormone comes along to change the gene expression?

They are degraded in proteosome after being ubiquitinated

4 types of reversible post translational modifications on nuclear receptors

Phosphorylation Acetylation Ubiquitination Sumoylation

Ubiquitination, sumoylation, and acetylation typically compete for ______ residues on NRs

Lysine (K)

Phosphorylation is a PTM that typically occurs at _____ residues on NRs

S/T