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43 Cards in this Set

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short term extracellular regulation by hormones and other factors
(seconds-minutes)
due to changes in activity of pre-formed enzyme/protein

no change in protein content

change in SPECIFIC ACTIVITY (activity per mol of polypeptide)
Long-term extracellular regulation by hormones and other factors
(hours-days)

accomplished by CHANGES IN PROTEIN CONTENT per cell (and sometimes by an ongoing change in specific activity)
coordinate regulation is often seen between pathways that...
use or generate common intracellular metabolites
reciprocal regulation is often seen between what kind of pathways?
competing pathways:

e.g.
gylcogenolysis/glycogen synthesis,
FA synthesis/FA oxidation, gluconeogenesis/glycolysis
extracellular regulation is directed by:
1. METABOLIC SUBSTRATES in the EC milieu (e.g. glucose, lactate, fatty acids)

2. HORMONES in the EC milieu (whose secretion rates in turn may be determined by a metabolic substrate)

3. Coordinate action of both hormone and substrates (coordination ensures that action(s) of hormones are appropriate to availability/non-availability of substrate)
functional elements required for a cellular response to a particular hormone/substrate
-hormone receptor,
-"post-receptor" signalling elements
- regulated protein

*[hormone/metabolite] normal and in bioactive conformation
mechanisms of "short-term" change in protein fxn by hormones and other factors:
change in [allosteric effector]

change in covalent modification of protein (e.g. phosphorylation)

change in intracellular localization

change in protein: protein association
mechanisms of "long-term" change in protein fxn by hormones and other factors:
change in rate of gene transcription

change in rate of mRNA turnover

change in rate of mRNA translation

change in rate of protein degradation
protein phosphorylation can result in the following changes in function:
-enzyme specific activity
-protein binding
-binding of proteins to DNA
-ability of Transcription factors to regulate gene expression
-intracellular localization of proteins
protein kinases
catalyze the attachment of a phospate (phosphorylation) of a protein
donor of phosphate group in protein phosphorylation
usually gamma-phosphate group of ATP (sometimes GTP)
protein phosphorylation reactions are

reversible or irreversible
IRREVERSIBle
Phosphoprotein phosphatases do what?
DEPHOSPHORYLATION (remove phosphate), liberating protein and inorganic Pi
types of protein kinases (what aa residues do they phorphorylate)
(> 500 kinases encoded in human genome)

some specific for serine/threonine

other only catalyze phosphorylation of tyrosite
types of phosphoprotein phosphotases
some specific for phosphoserine/phosphothreonine

and others for phosphotyrosine
"multi-site" phosphorylation
describes the presence of different "sites" of phosphorylation on a particular protein, that are catalyzed by different kinsases/phosphatases

explains complicated regulation of protein function
amplification potential of protein kinase
1. Each kinase (or phosphatase) can catalyze the phosphorylation (dephosphorylation) of many substrate polypeptide molecules

if the phosphorylated (dephophorylated) substrate is an enzyme that is activated by such modification...

each enzyme in turn can generate many substrate products

2. ACTIVATED ENZYME(s) MAY HAVE KINASE/PHOSPHATASE ACTIVITY Many protein kinases/phosphatases are subject to covalent modification by phosphorylation: this created "cascades" of kinase and phosphatase activation/inactivation which also contributes to further amplification
glucose regulation of glycogen synthesis/degradation
involves altered enzyme phosphorylation of:
glycogen synthase
and
glycogen phosphorylase
(IN LIVER CELL)
effect on low blood glucose (or decreased cellular ATP) on AMPK (and its effects)
low [glucose] --->(+) AMPK

AMPK ---> (+) ATP generation
and ---> (-) ATP utilization

NET EFFECT: (+) cellular ATP

---> (+) ATP generation via:
(+) FA oxidation and (+) cellular glucose uptake

---> (-) ATP utilization
(-) FA and sterol synthesis
(-) cell division (postponed, bc of high energetic cost)
regulation of de novo FA synthesis by plasma fatty acid involves
allosteric regulation of:
acetyl-CoA carboxylase
(in liver cell and adipocyte)
AMPK
AMP activated protein kinase

acts as metabolic sensor that "reads" availability of ATP and alters rate of ATP generation or utilization appropriately
AMPK is activated by what?
when glucose or oxygen is decreased

cellular ATP is decreased (5'-AMP levels rise)

AMPK is activated:
+ATP generation
-ATP utilization
"counter-regulatory hormones"
hormones that are antagonized by insulin:
glucagon
alpha-adrenergic catecholamines (norepinephrine)
beta-adrenercic catecholamines (epinephrine)
vasopressin
cortisol
thyroid hormone
growth hormone
hormones that bind EXTRACELLULARLY to a receptor on the plasma membrane
insulin
the catecholamines
vasopressin
glucagon
hormones that bind to INTRACELLULAR receptors

requiring hormone uptake by cell
cortisol
thyroid hormone
what are transcription factors?
intracellular hormone receptors (eg for cortisol and thyroid hormone)

that bind DNA and regulate gene expression

LONG TERM REGULATION
time frame of regulation initiated by cell-surface receptors
BOTH short and long term regulation
types of signaling from cell-surface receptors (OUR FOCUS)
Receptor Kinases (insulin, growth factors)
G-Protein Coupled Receptors (peptides, neurotransmitters, postaglandins)
types of events regulated by cell surface receptors
altered protein phosphorylation:
(then a post-receptor mechanism effects intermediate metabolism)
-cellular trafficking
-enzymes (activated or inhibited)
-protein synthesis
-membrane effects
- DNA/RNA synthesis
glucagon and epinephrine bind to what kind of receptor?
G protein-coupled receptors

linked to adenylate cyclase/cAMP
Components of G-protein coupled receptor
receptor
+ heterotrimeric G protein
+ effector (eg Adenylate Cyclase)
extracellular binding of hormone does what to G-protein in GPCR
leads to displacement of GDP bound tby GTP on G protein

dissociation of the receptor associated G protein into free alpha and beta/gamma subunits
GTP-bound alpha subunit of G protein
activates AC, leading to formation of cAMP from ATP
GDP-bound alpha subunit of G protein
associates with beta/gamma subunit, inactive
cAMP (in GCPR pathway)
2nd messenger

formed by adenylate cyclase (activated effector)

binds to the regulatory subunit of cAMP-dependent protein kinase, liberating its catalytic subunit, which can then phosphorylate key substrates
OFF singals of GCPR/cAMP pathway
1. INTRINSIC GTPase of G protein alpha subunit (hydrolysis of GTP to GDP allows reassociation of heterotrimer, terminating signal)

2. Activity of cAMP PHOSPHODIESTERASE
breaks down cAMP to AMP
activation of this enzyme by insulin is one way in which insulin antagonizes the action of hormones that work through this pathway
"steady state" of intracellular [cAMP} determined by:
competing activities of adenylate cyclase and cAMP phosphodiesterase
Phospholipase C is activated by what kind of signal
a "free" GTP-bound alpha subunit of receptor associated G protein
Phospholipase C pathway is activated by what hormones?
alpha adrenergic catecholamines (norepinephrine)

vasopressin
what does active phospholipase C do?
cleaves PIP3 into:
IP3 (inositol-3-phosphate) and
DAG (diacylglycerol)

part of PLC pathway,
IP3 leads to liberation of Ca++ from internal stores
DAG, IP3 and Ca++ (act as 2nd messengers and) activate downstream protein kinases
off signals of PLC pathway
1. GTPase of G protein alpha subunit (hydrolysis of GTP to GDP which allows reassociation of the heterotrimer, terminating the signal)
IP3
inositol-3-phosphate

along with DAG, product of cleavage of PIP3 by activated phospholipase C

induces the release of intracellular Ca2+ stores

along with Ca2+ and DAG activates downstream protein kinases
DAG
diacylglycerol

along with IP3, product of cleavage of PIP3 by activated phospholipase C

along with Ca2+ and IP3 activates downstream protein kinases in PLC pathway