BCM - Hormone Signaling Pathways

Question 1

What is endocrine signaling?

Answer 1

When a signaling molecule is released by a cell distant from its target and is transported via the blood stream to the target cell

Ex: epinephrine

Question 2

What is paracrine signaling?

Answer 2

When a signaling molecule released by one cell diffuses to a neighboring target cell

Ex: Testosterone

Question 3

What is autocrine signaling?

Answer 3

When a signaling molecule acts on the same cell that it is secreted from.

Ex: Interleukin-1

Question 4

What is juxtacrine signaling?

Answer 4

When a signaling molecule stays attached to the secreting cell and binds to a receptor on an adjacent target cell

Ex: Heparin-binding epidermal growth factor

Question 5

How do hydrophilic and hydrophobic hormones compare in terms of half life?

Answer 5

Hydrophilic hormones have very short half lives, seconds to minutes

Hydrophobic hormones have longer half lives, hours to days

Question 6

Where does the G protiein get its name from?

Answer 6

G protein receptors have intrinsic GTPase activity, which allows it to deactivate itself by hydrolyzing the GTP to GDP and Pi

Question 7

What specific enzymes/proteins activate and deactivate G Proteins?

Answer 7

Guanine Exchange Factor (GEF) - Causes activation by hydrolyzing Exchanging a Phosphate group from one GTP molecule to the GDP moelcule bound the Alpha Subunit, forming GTP-bound activated Alpha Subunit

GTPase Activating Protein (GAP) - Causes deactivation by hydrolyzing the GTP bound to the Alpha subunit into GDP

Question 8

Describe the secondary messenger cascade of Gs GPCRs

Answer 8

Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit

Activated alpha subunit then activates membrane-bound Adenylyl cyclase

Adenylyl cyclase converts ATP to cAMP

cAMP activates PKA

PKA phosphorylates target proteins

Question 9

Describe the secondary messenger cascade of Gi GPCRs

Answer 9

Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit

Activated alpha subunit then inactivates the membrane-bound Adenylyl Cyclase

This inhibits cAMP from being produced and thus also prevents activation of PKA

Question 10

Describe the secondary messenger cascade of Gq GPCRs

Answer 10

Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit

Activated alpha subunit then activates Phospholipase C (PLC)

PLC then activates PIP2, causing it to split into IP3 and DAG

IP3 causes an increase in intracellular Ca2+

Intracellular Ca2+ and DAG both activate PKC, which phosphorylates target proteins

Question 11

Describe the secondary messenger cascade of Gt GPCRs

Answer 11

Light activates the GPCR, causing the GDP on the alpha subunit to be converted to GTP, activating the subunit

Activates alpha subunit then activates cGMP PDE (phosphodiesterase) which converts cGMP to 5’-GMP

Question 12

What are some structural features of insulin?

Answer 12

Insulin is made up of two polypeptide chains (an A chain and a B chain)

There are two disulfide bonds connecting the two chains

There is a third disulfide bond found within the A chainf

A chain is shorter than B chain

Question 13

Describe the process of insulin synthesis and secretion

Answer 13

Preproinsulin mRNA is translated into preproinsulin protein

Preproinsulin is transported to the ER lumen

Protease cleaves preproinsulin, forming proinsulin

Proinsulin is folded and transported to the Golgi

While in the Golgi, the proinsulin is packaged into granules

Within the granules, proteases cleave the proinsulin, forming a collection of insulin and C peptides

While stored in the granules, insulin forms into hexameric crystals (3 dimers bound together)

When Beta cell is signaled to do so, insulin and C peptide are secreted together into the blood.

Question 14

What are the two phases of insulin secretion?

Answer 14

Readily Releasable Pool (RRP) - first release (less than 5% of stored insulin) is rapidly secreted upon stimulation by glucose

Reserve Pool - second release (95% of stored insulin) granules must be mobilized before they canbe secreted

Question 15

How does insulin get secreted?

Answer 15

Glucose causes ATP to increase

Increased ATP inhibits ATP sensitive K-ATP channels

Inhibition of K-ATP channels causes membrane depolarization, activating Ca2+ channels

Ca2+ enters the cell causing insulin granules to be secreted

Question 16

How does insulin signaling cause Glucose uptake in cells through the RAS independent pathway?

Answer 16

Insulin binds to Receptro Tyorsine Kinase, causing dimerization of the receptor and phosphorylation fo tyrosine kinase domains.

Active tyrosine kinase domains phosphorylate, thus activating, IRS-1

Activated IRS-1 recruits PI 3-kinase

PI 3-kinase activates PKB

PKB phosphorylates target proteins which promotes GLUT4 movement to plasma membrane (in muscle and adipose cells) and promotes glycogen synthesis

Question 17

What is the RAS-dependent pathway of insulin signaling?

Answer 17

Insulin binds to Receptor Tyrosine Kinase, causing dimerization and autophosphorylation of intrinsic tyrosine kinase domains

Activated tyrosine kinase domains phosphorylate IRS-1

Activated IRS-1 recruits GRB-2

GRB-2 activates RAS and MAP kinase pathway

Results in activation of Glucokinase enzyme, thus promoting glycolysis and glycogen synthesis

Question 18

How is insulin signal terminated?

Answer 18

Receptor is internalized in target cells by endocytosis

Is either destroyed or recycled back to the plasma membrane

Question 19

What is insulin resistance?

Answer 19

Failure of normal amounts of insulin to elicit the uptake of an adequate amount of glucose

Can be caused by downregulation of insulin receptors or defects in insulin signaling (inability to move GLUT4 transporters to plasma membrane in target tissue)

Question 20

What are orphan receptors?

Answer 20

Nuclear receptors found by DNA sequencing, whose ligands have yet to be discovered

When a ligand to an orphan receptor is discovered, it becomes an “adopted” orphan receptor

Question 21

What are the domains that make up nuclear receptors?

Answer 21

Ligand Binding Domain (LBD)

Activation Function 1 Domain (AF1)

DNA Binding Domain (DBD)

Question 22

Distinguish the Estrogen Receptors

Answer 22

ER-alpha (first to be discovered) is expressed most abundantly in the female reproductive tract (especially the uterus, vagina, and ovaries)
- Also expressed in mammary glands, hypothalamus, endothelial cells, and vascular smooth muscle

ER-beta is expressed most abundantly in the ovaries and prostate
- Also expressed in lung, brain, bone, and vasculature

Many cells express both receptors

Question 23

How estrogen signaling work?

Answer 23

Estrogen binds to nuclear receptor, causing dimerization.

Dimerization promotes HAT (Histone Acetyl Transferase) activity - promotes gene expression

HAT activity activates transcription

Question 24

What is Tamoxifen and how does it work?

Answer 24

Is an estrogen antagonist, used to treat breast cancer

Tamoxifen is metabolized by liver Cyt P450 to 4-hydroxy-tamoxifen, which binds to ER and promotes HDAC (Histone Deacetylase) activity

HDAC activity inhibits transcription