chapter 16 biochem
Advantages of second messengers include that:
- the signal can be amplified by making many second messengers. - second messengers can freely diffuse to other sites within the cell. - a few common second messengers can be used in multiple signaling pathways.
enzyme cascade
a sequence of successive reactions that cause enzymes to undergo conformational transitions that switch them from their inactive to their active forms , or vice versa, while simultaneously amplifying the original signal
how does cAMP molecules signal amplification
cAMP diffuses into the cytoplasm and binds and activates c-AMP-dependent protein kinase
the G protein G(s) stimulates
cAMP production when glucagon, TSH and epi bind their recpeptors
Examples of second messengers include:
cAMP, calcium ion, and diacyl glycerol
what does the beta and gamma subunit promote
association of the alpha subunit with the GPCR and prevents GDP/GTP exchange
guanylate cyclase is activated by
atrial natriuretic peptide and bacterial enterotoxin
PKB is controlled by an
autoregulatory pathway
what is cholesterol used to make
bile acid
Most signal molecules:
bind to membrane receptors and transmit information across a membrane without traversing the membrane
how does interleukin 2 regulate immune system
binds to activated T cells to make numerous identical T cells
How are hydrophobic hormones transported in the blood?
by attaching to transport proteins (albumin and sex hormone-binding protein)
The ___________ molecule functions as a secondary messenger.
cAMP
Which of the following compounds can act as second messengers in signal transduction pathways?
cyclic AMP
cAMP
cyclic AMP; a second messenger molecule synthesized from ATP by adenylate cyclase
leading cause of death in the US that afflicts 7% of population
diabetes
When insulin binds to its receptor, which of the following occurs?
A PIP2-dependent kinase is activated.
IP3 diffuses to the calcisome (SER) where it binds to a
calcium channel causing the release of calcium
The binding of IP3 to the IP3 receptor results in the release of ___________ from the endoplasmic reticulum.
calcium ion
what are other second messengers
calcium ions, cGMP, and phosphatidylinositol components
The ____________ protein binds to calcium ions and serves as a Ca2+ sensor in eukaryotic cells.
calmodulin
when hydrophobic hormones molecules reach their target they
can diffuse through the plasma membrane and bind intracellular receptors
_________________ is a secondary messenger and is abbreviated IP3.
inositol 1,4,5-triphosphate
27 type 2 diabetes is caused by an insensitivity to
insulin
AMPK is inhibited by
insulin and leptin binding to their receptors
35 the binding of insulin to its receptor on the surface of a target cell activates the receptors tyrosine kinase activity, which in turn causes several phosphorylation cascades that alter the activity of numerous enzymes as well as the expression of specific genes. Describe how one of these phosphorylation cascades stimulates glycogen synthesis
insulin receptor substrate 1 (IRS-1) is one of the substrates of activated insulin receptor phosphorylation reactions. once it is phosphorylated, IRS-1 activates several proteins, including PI3K which subsequently phosphorylates PIP2 a minor component of the cell membrane yielding PIP3. once PIP3 has bound to PDK1, the activated protein proceeds to phosphorylate several kinases, including PKB. Activated PKB stimulates glycogen synthesis by contributing to the activation of glycogen synthase. It does so by inactivating GSK3, one of several kinases that inhibit glycogen synthase
26. type 1 diabetes is caused by the destruction of
insulin-producing pancreatic B- cells
examples of cytokines
interleukins and interferons
bacterial enterotoxin activates another type of guanylate cyclase in
intestinal cells and causes diarrhea
epidermal growth factor
is a mitogen (stimulator of cell division) for a large number of epithelial cells. triggers cell division of epidermal and gastrointestinal lining cells by binding TKRs
How does the binding of a hormone to receptor activate a G-protein?
it causes an exchange of GTP for bound GDP
how are the chemical signals in intracellular communication happen once released
it is released into extracellular environment and each chemical signal is recognized by a specific cell (target cell)
31 elevated concentration of blood ketones is referred to as
ketoacidosis
glycogen is depleted after several hours, so how does gluconeogenesis play an important role
large amounts of amino acids from muscle protein are used after several week the brain will becomes adapted to using ketone bodies as an energy source
G-protein coupled receptors
largest known receptor family that are composed of seven membrane spanning helices
glucosuria
leads to osmotic diuresis causes frequent urination and excessive thirst
N-terminus has a domain for
ligand binding
G- protein activation occurs when
ligand binds the GPCR
the phospholipids, lipids, and proteins are incorporated into _________________ for export to tissues
lipoproteins
chylomicron remnants will deliver the phospholipids, cholesterol and the rest of triacylglycerol molecules to the
liver
additional fatty acids from adipose tissue and ketone bodies from the liver are
mobilized
what are G proteins used for
molecular switches that transduce ligand binding to intracellular signals
G proteins attach to the membrane by
myristoyl and or palmitolyl groups
how do animals prevent excess hormone synthesis and release
negative feedback
in animals what is responsible for controlling metabolism
nervous and endocrine systems
insulin and the hypothalamus reduce intake via the same
neurons
GPCRs respond to
neurotransmitters and hormones
A G(3) undergoes GDP/GTP exchange
once the ligand binds to the receptor
cytokine
one of a set of hormone-like polypeptides that stimulate or inhibit cell growth or proliferation; a term traditionally used in reference to proteins produced by blood-forming cells and immune system cells
g protein
one of the set of heterotrimeric GTP-binding proteins; a protein that binds GTP, which activates the protein to perform a function
in mammals many metabolic activities are controlled by
peptide hormones
phosphorylated IRS1 then binds and activates proteins like
phosphatidylinositol-3-kinase which phosphorylates PIP2
The enzyme responsible for induction of the phosphoinositide cascade is:
phospholipase C
_______________: The enzyme that catalyzes the cleavage of PIP2.
phospholipase C
hormone receptor complex activates the g protein that activates
phospholipase C
Phospharidylinositol-4,5-bisphosphate is cleaved by
phospholipase C into DAG and IP3
fatty acids are used to synthesize
phospholipids
PKC (protein kinase C)
phosphorylates key cell signal regulatory enzymes
PIP3 then triggers a kinase cascade including
pkb activation
IGF-1 and IGF-2 are
polypeptides that mediate the growth promoting action of growth hormone
13 growth factor
polypeptides that stimulate cells to grow and or undergo cell division
interleukin 2
promotes cell growth and differentiation and regulates the immune system
Type 1 interferons
protect cells from viral infections by phosphorylating and inactivating a protein necessary for protein synthesis (eIF2alpha)
The mechanism by which insulin-signaling processes might be terminated include:
protein dephosphorylation by phosphatases
The enzyme that becomes active when bound to cAMP is _ ________________.
protein kinase A (PKA)
The ____________ enzyme becomes active when bound to Ca2+ and diacylglycerol.
protein kinase C (PKC)
insulin receptor substrate 1 is one of the
proteins phosphorylated by the insulin receptor
in youth, illness and pregnancy the animals tissues exist in a metabolic
ready state
hormones response element
receptor ligand complex migrates to the nucleus as a homodimer that binds to a ______________________ and activates transcription
growth factors
rigorous control of cell growth and cell division is essential for survival of multicellular organisms
what does adenylate cyclase produce
second messenger cAMP
33 a group of molecules called __________ mediate the actions of many hormones
second messengers
what are intracellular actions often triggered by
second messengers cAMP
The membrane-bound receptor in G protein-coupled signal transduction is quite separate to the effector enzyme which catalyses the formation of an intracellular _____________
secondary messenger
platelet derived growth factor
secreted by blood platelets during the clotting reaction. stimulates mitosis and collagen synthesis in fibroblasts during wound healing
how does the CNS regulate the complex cascade
sensory signals are received by the hypothalamus and area of the brain that integrates the nervous and endocrine systems
7TM is an abbreviation for _______________ receptors.
seven-transmembrane helix
what propels the food along the tract and is controlled by sympathetic and parasympathetic nerves
smooth muscle
What are the two messenger products formed by cleavage of PIP2?
diacylglyercol and inositol 1,4,5-triphosphate
63 describe the effects of a diet that includes large amounts of fructose
diets high in fructose may result in obesity, blood dyslipidemia, hypertension, and insulin resistance. metabolic syndrome is a term used to describe this cluster of disorders
24 the reduction in the numbers of cell surface receptors in response to stimulation by their specific hormone molecule is called ______________
downregulation
how is the consuming of food intermittently how is this possible
due to the elaborate mechanism for storing and mobilizing energy-rich molecules that are derived from food
32 the two major types of cell-surface receptors that bind to hormone molecules are G protein-linked receptors and _______________ recpetors
enzyme linked
how is the feeding phase controlled
enzyme producing cells of the digestive organs, nervous system, and several hormones
examples of growth factors
epidermal growth factor, platelet-derived growth factor, insulin like growth factor 1 and 2
Which of the following is an extracellular messenger involved in signal transduction?
epinephrine
_______________: The primary messenger responsible for the "fight or flight" response.
epinephrine
______________ binds to β-andrenergic receptors.
epinephrine_(adrenaline)
lack of cellular glucose causes
fatigue and activation of the inflammatory network
what does the feeding phase involve
food movement digestion absorption in the blodd and lymph in GI tract
insulin release triggers
glucose uptake glycogenesis fat synthesis and storage gluconeogenesis stimulates protein synthesis
pkb stimulates
glycogen synthesis and inhibits lipolysis
PKB activates mTOR which is a central kinase sensor that integrates
hormonal activity, nutrient availabilty, stress and energy status
in feeding behavior the regulation of feeding behavior involves
hormone and neuronal signals as well as sensory input from the environment (5 senses). both are integrated in the brain to regulate appetite
AMPK seems to mediate the appetite-regulating integration of the
hypothalamus
where are the primary neural circuits controlling appetite are in the
hypothalamus
how are peptide hormones controlling mammal metabolic activities
they intitiate their action by binding to the receptors on the outer surface of the targets cells plasma membrane
Protein kinase A phosphorylates serine and ____________ residues.
threonine
Which of the following does NOT belong to a receptor tyrosine kinase family?
thyroid receptor
an example of regulation by the endocrine system
thyroid-stimulating hormone (TSH) stimulates follicular cells from the thyroid to release T3 (stimulates glycogenolysis in the liver)and T4
chylomicrons pass to the bloodstream what does this provide to the muscle and adipose tissue
triacylglycerol
G proteins are membrane-bound proteins that bind GDP when inactive True or false
true
37 extreme thirst is a characteristic of diabetes. Explain
in uncontrolled diabetes, large amounts of glucose are excreted in the urine. Excessive urine flow is caused by the large amounts of water that are excreted along with the glucose and results in dehydration of the body. dehydration then usually triggers the thirst response
atrial natriuretic peptide is released by heart cells to respond to
increased blood volume and lowers blood pressure via vasodilation and diuresis
insulin dependent diabetes mellitus
type 1 diabetes inadequate amounts of insulin are secreted. autoimmune disease that leads to the B cells of the pancreas being destroyed
example of downregulation
type 2 diabetes is due to a decrease in functional insulin receptor (insulin resistance)
noninsulin dependent diabetes mellitus
type II diabetes caused by insensitivity of target cells to insulin
The cytosolic side, or β subunit, of the insulin receptor is a ________ kinase.
tyrosine
binding of ligand to the external domain activates
tyrosine kinase domain insulin receptor has two domains the extracellular a and the B. which has a transmembrane domain and the tyrosine kinase domain
Which of the following amino acids can be phosphorylated?
tyrosine, serine, threonine
when are anabolic and catabolic reaction pathways that use carbs, lipids, and proteins as energy and biosynthetic precursors not precisely regulated
youth, illness, pregnancy
Type 2 diabetes
-caused by insulin resistance, most commonly due to downregulation of insulin receptor (obesity increases risk) - diet and exercise are good treatments -having other serious medical condition hyperosmolar hyperglycemic non-ketosis can occur
how does each organ in the mammalian body contributes to the individual's function in several ways how?
-consumers of energy or supplying energy rich nutrients -signal molecules offer an important control mechanism for integrating these processes -nutrient transport across cell plasma membranes is also an important feature of organ function
type I diabetes
-destruction of insulin producing B cells by the immune system -symptoms occur abruptly with the most serious symptom being ketoacidosis
50. several hormones may activate the same G protein. therefore different hormones may have the same or similar effect. For example, glycogen degradation is initiated by both epi and glucagon. why is overlap of function an advantage
-glucagon is released into the blood when blood glucose levels are low between meals. - epi is released under threatening circumstances, triggers the quick release of glucose into blood. the overlap in function of these and other sets of hormones allows an effective response to what may be subtle differences in physiological conditions
what are humans predisposed to obesity in modern world
-have gone from physically challenging hunter-gatherer and agrarian lifestyles to sedentary lifestyle with cheap calorie dense food (fructose introduced) - leptin or leptin receptor mutations can lead to overeating
symptoms of diabetes
-hyperglycemia leading to glucosuria and osmotic diuresis -dyslipidemia abnormal blood lipid and lipoprotein levels
38 briefly discuss the major classes of second messenger that are currently recognized
1. cAMP- generated from ATP by adenylate cyclase which stimulates changes in cellular activities by activating PKA 2. cGMP- generated from GTP by guanylate cyclase which activates protein kinase G 3. diacylglycerol - DAG a product of phospholipase C which activates kinase C 4. inositol-1,4,5 triphosphate- IP3 a product of phospholipase C which triggers the release of Ca2+ from the calcisome 5. calcium ions which regulate the activities of numerous cellular activities when they bind to calcium dependent regulatory proteins
60 explain why a diet high in fructose is a major contributing factor in athersclerosis
1. dyslipidemia, a consequces of hepatic fructose metabolism. 2. glycation reaction that occur about 7x as often with fructose as those of glucose and lead to advanced glycation end product AGE formation
metabolic syndrome
A syndrome marked by the presence of usually three or more of a group of factors (as high blood pressure, abdominal obesity, high triglyceride levels, low HDL levels, and high fasting levels of blood sugar) that are linked to increased risk of cardiovascular disease and Type 2 diabetes.
mTOR regulates
ARC nutrient-sensing neurons
_____________ is the membrane protein that catalyzes the conversion of ATP to cAMP.
Adenylate cyclase
what unit of the G protein binds to GTP
Alpha
which units inhibit the alpha subunit
B and Gamma
glucose movement from the small intestine to the liver stimulates ______________ in the pancreas to release ________________
B-cells, insulin
the synthesis and secretion of peptide hormones are regulated by a complex cascade controlled by the
CNS
How does binding of epinephrine initiate the cAMP production? Discuss briefly in terms of receptor structure and function.
Epinephrine binds to a 7TM receptor which interacts with heterotrimeric G protein, causing it to exchange GDP with GTP. The binding of GTP causes the G protein to dissociate and the active Gα-GTP complex binds to the enzyme, adenylate cyclase. Adenylate cyclase is a large membrane-embedded protein, with two large domains located on the inside of the cell. This interaction induces a conformational change in the enzyme, resulting in a more catalytically active form; thus, more cAMP is made. See Figure 13.4 of the textbook for more detail.
hormone action is ultimately controlled by the cells that secrete the hormone True or False
False
__________: The subunits of heterotrimeric G proteins are anchored to the cell membrane by being covalently linked to these types of molecule.
Fatty acids
what are the two types of receptors that water soluble hormone molecules bind to
G protein coupled receptors and receptor tyrosine kinases
C-terminus has a segment for interacting with
G proteins
Which form of the guanyl nucleotide is bound in the unactivated state?
GDP
GTP hydrolysis mediated by
GTPase activating protein inactivates the G protein (GDP-a(3)
What is the difference between heterotrimeric G proteins and small G proteins?
Heterotrimeric G proteins are composed of αβγ subunits. The α subunit contains the guanyl nucleotide binding site. Upon activation by the signal-receptor event, the GDP is exchanged with a GTP, and the βγ subunits dissociate from the α bound with GTP, which is the form that activates adenyl cyclase. Small G proteins, such as Ras, are single-subunit proteins. They are activated by proteins such as Sos in the EGF signal pathway. The activation causes the exchange of GDP for GTP to convert it into an active kinase.
in addition to stimulating cell division what is the same metabolic processes as insulin
IGF-1 and IGF-2
when GH binds to its cell surface receptor what are the stimulators of growth in animals
IGF-1 and IGF-2
8. NADH is an important reducing agent in cellular catabolism, whereas NADPH is an important reducing agent in anabolism. Review previous chapters and identify how the synthesis and degradation of these 2 molecules are interconnected
NADPH which is formed during the PPP and reactions catalyzed by isocitrate dehydrogenase and malic enzymes, is used as a reducing agent in a wide variety of synthetic reactions. The degradation of some of these molecules results in the synthesis of NADH, a major source of the cellular energy via the mitochondrial electron transport system.
phosphatidylinositol cycle
PIP2 is cleaved by phospholipase C to form DAG and IP3 mediates, primarily via Gq proteins, the action of hormones and growth factors
Describe the role of phosphoinositol 4,5-bisphosphate (PIP2) in insulin signal transduction.
PIP2 is one of the signal molecules in the insulin pathway. It is converted into PIP3 by phoshoinositide 3-kinase. The binding of PIP3 activates PIP3-dependent protein kinase, which phosphorylates and activates other kinases in the pathway.
Describe how phosphatidylinositol-4,5-diphosphate is converted into two secondary messengers.
Phosphatidylinositol 4,5-diphosphate (PIP2) is hydrolyzed by phospholipase C to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The DAG binds to and activates protein kinase C, and the IP3 binds to a receptor that opens Ca2+ channels allowing Ca2+ to be released from the cellular stores.
example of negative feedback
T3 and T4 inhibit TSH release
What happens when signaling paths are not terminated properly?
The cell will not be able to respond properly to new stimuli. The errant signals may lead to cancer, uncontrolled cell growth, or other problems.
How is the hormone-bound activated receptor reset after activation?
The hormone dissociates, and the receptor returns to its initial, unactivated state. It may rebind the hormone, depending on the concentration in the environment.
What are some of the common structural features of the receptors to which signal molecules bind?
The molecule must have signal binding site on the extracellular side of the membrane, And must have an intracellular domain. Binding of the ligand to the receptor must induce Change into another form (transduced) that affects the shape of the intracellular portion So the signal can be transmitted
What is the general mechanism for signal transmission by 7TM receptors?
The receptors "snake" through a membrane, with domains extending on the extracellular and cytoplasmic sides. A ligand binds to a site on the extracellular side, inducing a conformation change that is detectable on the cytoplasmic side of the cell.
What are receptor tyrosine kinases? Provide an example.
These are proteins that bind ligands, such as EGF or insulin, on the extracellular domain. They also contain tyrosine kinase domains on the intracellular side.
What is a disadvantage of using common molecules for signaling paths?
When second messengers are involved in more than one signaling pathway, fine tuning and sensitive responses can result. However, when the cross talk becomes inappropriate, the signaling paths and responses will be in error
DAG (diacylglycerol)
a second messenger molecule in the phosphatidylinositol pathway that activates protein kinase C
IP3 (inositol 1,4,5-triphosphate)
a second messenger molecules in the phosphatidylinositol pathway that binds to IP3 receptor, a calcium channel
G- protein coupled receptor
a cell surface receptor that transduces the binding of a hormone or other signal molecule into an intracellular response via the activation of a G protein
receptor tyrosine kinases
a family of transmembrane receptors that bind ligands such as insulin and epidermal growth factor
PIP2 (phosphatidylinositol 4,5-bisphosphate)
a minor membrane phospholipid that is cleaved by phospholipase C
second messenger
a molecule that initiates the intracellular action of some hormones
tropic hormone
a molecules that stimulates an endocrine gland to secrete its hormones
activated adenylate cyclase synthesizes
a number of cAMP molecules (signal amplification)
desensitization
a process in which target cells adjust to changes in stimulation by hormone molecules by decreasing the number of cell surface receptors or by inactivating those receptors
interferons
act as growth inhibitors and are produced by a variety of cells in response to anitgens, mitogens, viral infection and certain tumors
Phosphatidylinositol cycle, DAG and Calcium mediate
action of hormones and growth factors ex: acetylcholine, TSH, vasporessin, GRH an epi
PKA then phosphorylates and alters
activity of key regulatory enzymes
GTP-a (i) inhibits
adenylate cyclase
GTP-a(s) activates
adenylate cyclase
GTP-a(3) subunit dissociates and activates
adenylate cyclase to produce cAMP
postabsorptive
after an overnight fast when nutrient levels are low
what are G protein composed of
alpha, Beta, and gamma units
what do second messengers often act to modulate
an enzyme cascade in order to amplify the signal response
36 bodybuilders often consume anabolic steroids to increase their skeletal muscle mass. how does these steroid molecules achieve this effect?
anabolic steroid hormones change the expression of a specific set of genes that code for proteins that increase protein synthesis in skeletal muscle
depending on the signal (peptide hormone) produced by the ARC can lead to
appetite suppression or stimulation
where are primary neurons in
arcuate nucleus (ARC)
Type 2 interferons
are produces by T lymphocytes and inhibit the growth of cancer cells
how does the g-protein activation occur when the ligand binds to GPCR
causes conformational change leading to GDP/GTP exchange, mediated by a guanine nucleotide exchange factor followed by a GTP-alpha subunit dissociation
In steroid and thyroid hormones mechanisms signal transduction pathways of the hydrophobic steroid and thyroid hormones result in
changes in gene expression
how does intracellular communication occur
chemical signals
how are most lipid molecules transported in the lymph as
chylomicrons
59 during periods of fasting, some muscle protein is depleted. how is the process initiated and what happens to the amino acids in these proteins?
during the initial phase of prolonged fast, blood glucose and insulin levels fall and glucagon release is triggered. glucagon acts to prevent hypoglycemia by promoting glycogenolysis and gluconeogenesis. alanine and glutamine are released as a result of the breakdown of muscle protein. Both amino acids are delivered to the liver where alanine undergoes a transamination reaction that yields pyruvate, a substrate for gluconeogenesis. glutamine is also a substrate for gluconeogenesis via the TCA cycle and conversion into oxaloacetate.
basic feature of diabetes
dysfunctional fuel metabolism
64 after about 6 weeks of fasting, the production of urea is decreased. explain
for several weeks after the onset of fasting, blood glucose levels are maintained via gluconeogenesis. during the most of this period, amino acids derived from the breakdown of muscle proteins are the major substrates for this process. eventually as muscle becomes depleted, the brain switches to ketone bodies as an energy source. Consequently, the production of urea (the molecule used to dispose of the amino groups of the amino acids) decline
what hormones are used in the smooth muscle contraction v
gastrin, secretin, and cholecystokinin (CCK)
regulation by the endocrine system involves the release of hormones from ___________ into the ___________ which then travel to ______________
glands, blood, target cells
in the fasting phase what is released as glucose and insulin levels fall back to normal
glucagon
caMP target proteins are depending on cell
glucagon and epi both activate glycogen degradation in the liver in caMP-dependent fashion
When activated, the insulin receptor results in the mobilization of _____________ transporters to the cell surface.
glucose
diabetes mellitus
glucose transport is compromised, damage the entire body. metabolic diseases caused by insufficient insulin synthesis increased insulin destruction or ineffective insulin action. all-cause cells to fail at acquiring glucose from the blood.
if a fast becomes prolonged (overnight) what occurs
maintenance of blood glucose levels by fatty acid mobilization, alternative to glucose for muscle, conserving glucose for the brain
what is intracellular communication believed to play a significant role in maintaining
metabolic balance
long fasting like starvation leads to
metabolic changes to ensure adequate glucose availability for glucose- requiring cells
DAG product activates protein kinase C which activates
specific regulatory enymes
postprandial
state after a meal when nutrient levels are high
what is absorbed and transported in the portal blood to the liver in the early postprandial state
sugars and amino acids
cGMP
synthesized from GTP by guanylate cyclase
9. explain, in general terms, the roles of the nervous and endocrine systems in metabolism
the nervous system, a network of neurons and support cells, provides the body with a rapid and efficient mechanism for acquiring internal and external information. the endocrine system consists of specialized glands that produce hormones that regulate metabolism. Interactions between the nervous system and the endocrine system released hormones are responsible for integrating the body's metabolic processes to maintain homeostasis. Sensor signals are received by the brains hypothalamus, which integrates nervous and endocrine signaling mechanisms
downregulation
the reduction in cell surface receptors in response to stimulation by specific hormone molecules
what prevents hypoglycemia
the stimulation of glycogenolysis and gluconeogenesis in the liver