Lecture 4: Cell Signaling - Exam 5 Flashcards
What are Glucocorticoids?
Anti-inflammatory in all tissues, and control metabolism in muscle, fat, liver, and bone. They also affect vascular tone, and in the brain influence mood, behavior and sleep-wakefulness cycles.
Describe Glucocorticoid action.
Glucocorticoids diffuse across the plasma membrane and bind to the glucocorticoid receptor. In the absence of ligand, the receptor is bound to Hsp90 in the cytoplasm.
Glucocorticoid binding displaces the receptor from Hsp90 and allows the formation of receptor dimers.
The activated receptors translocate to the nucleus, bind DNA, and associate with coactivators with histone acetyltransferase (HAT) activity to stimulate transcription of their target genes.
What is the thyroid hormone well known for?
Controlling metabolism, growth, and many other bodily functions.
Describe the conditions in which the thyroid hormone binds DNA.
Thyroid hormone receptor binds DNA in either the presence or absence of hormone.
Thyroid hormone receptor binds DNA in either the presence or absence of hormone. However, hormone binding causes some changes. What are they?
Hormone binding changes the receptor from a repressor to an activator of target gene transcription.
In the absence of the hormone, what happens?
The receptor associates with corepressors with histone deacetylase (HDAC) activity.
In the presence of the hormone, what happens?
The receptor associates with coactivators with histone acetyltransferase (HAT) activity.
Local cell signaling is carried out via?
Membrane receptors that bind to proteins in the extracellular matrix or directly to receptors from a neighboring cell in a process called juxtacrine signaling.
One mechanism for long-range signaling is through?
Paracrine signaling, such that one cell secretes a signaling protein (ligand) into the environment and across the distance of many cells. Only those cells expressing this ligand’s corresponding receptor can respond, either rapidly through chemical reactions in the cytosol, or more slowly through the process of gene and protein expression.
Discuss the process of large heterotrimeric G proteins going from their inactive state to their active states.
In the inactive state, alpha is bound to GDP in a complex with beta and gamma.
Hormone binding to the receptor causes exchange of GTP for GDP.
The alpha and beta-gamma complex then dissociate form the receptor and interact with their targets.
The G protein is now in its active state, and will target enzymes and ion channels.
To get back to the inactive state, GTP hydrolysis takes place via RGS (a GAP) that hydrolyzes GTP to GDP.
What are second messengers?
Molecules that relay signals received at receptors on the cell surface - such as the arrival of protein hormones, growth factors, etc. - to target molecules in the cytosol and/or nucleus. (like cAMP)
How was the role of cAMP as a second messenger discovered?
Was discovered in 1958 by Sutherland in studies of epinephrine, which signals the breakdown of glycogen to glucose in muscle cells.
How is cAMP formed?
Is formed from ATP by adenylyl cyclase and degraded to AMP by cAMP phosphodiesterase.
*Adenylyl cyclase is activated by G protein!
Describe the regulation of glycogen metabolism by epinephrine.
Receptor stimulation by epinephrine leads to G protein-mediated activation of adenylyl cyclase.
cAMP activates protein kinase A, which consists of two regulatory (R) and two catalytic (C) subunits in its inactive form.
Binding of cAMP to the regulatory subunits induces a conformational change that leads to dissociation of catalytic subunits, which are then enzymatically active.
Protein kinase A activates phosphorylase kinase.
Then, phosphorylase kinase activates glycogen phosphorylase, which catalyze the breakdown of glycogen to glucose-1-phosphate.
Describe cyclic AMP-inducible gene expression.
Receptor stimulation leads to G protein-mediated activation of adenylyl cyclase, synthesis of cAMP, and activation of protein kinase A.
The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein), leading to the recruitment of coactivators and expression of cAMP-inducible genes.
