Hormones Biochemical classification Mechanism of action Hierarchy Feedback loops Signal...
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Transcript of Hormones Biochemical classification Mechanism of action Hierarchy Feedback loops Signal...
Hormones
• Biochemical classification
• Mechanism of action
• Hierarchy
• Feedback loops
• Signal transduction
PolypeptidesPolypeptides
SteroidsSteroids
Amino acid derivativesAmino acid derivatives
Insulinglucagonsomatotropin
FSHLHvasopressin
OxytocinthyrotropinACTH
Estrogentestosteronecortisol
AldosteronecorticosteroneProgesterone
Epinephrinenorepinephrinedopamine
Thyroxine, T3 and T4MelatoninSerotonin
Rule: All hormones interact with target cells by first binding to specific receptors located either onthe plasma membrane or as a cytosolic protein
Rule: The receptor for hormones must be linkedto a component that is able to respond to thebinding of hormone with its receptor
Rule: Substances that fool the responder intothinking a hormone has bound are call agonists
Rule: Substances that prevent the binding of thenatural hormone and do not elicit a response fromthe receptor are called antagonists
Cyclic AMP Cyclic GMP Ca2+ Diacylgycerol Proteinsubstrates
PK-A PK-G Calmodulin PK-CProtein Ser/Thr kinases
Protein substrates
Protein substrates
Protein substratesMultifunctional kinases
Otherphospholipases
1 2 3 4 5
11 2 3 4 5
Tyrosine kinase
IP3G G G G
InsulinGlucagon T-cellActivation
Nitricoxide
G protein
End result is phosphorylation ofone or more proteins
Hypothalamus
Anterior pituitaryPosterior pituitary
Thyrotropin
ACTH
Somatotropin
LH
FSHProlactin
Vasopressin
Oxytocin
ThyroidAdrenalCortex
AdrenalMedullaPancreas Ovary Testis
Muscles liver Tissues
Liver,muscles
Estradiol TestosteroneInsulin,glucagon,somatostatin
T3 Cortisolaldosterone
Mammary glands
Reproductive organs
Epinephrine
Releasinghormones
Nervous
Feedback Loops
Rule: Hormones elicit their own shut off mechanism
Hypothalamus
Corticotropinreleasing factor
AnteriorPituitary
-Corticotropin
Cortisol
AdrenalCortex+
+
Rule: All peptide hormones are synthesized asinactive “pre-pro” precursors
Rule: All peptide hormones are synthesized asinactive “pre-pro” precursors
Rule: A signal peptide must be cleaved off to activate the mature form of the hormone
Rule: A signal peptide must be cleaved off to activate the mature form of the hormone
Signal Transduction
Definition: The series events and components thattake part in transmitting a hormonal signal to athe interior of the cell
Definition: The series events and components thattake part in transmitting a hormonal signal to athe interior of the cell
Membrane or cytosolic Receptor
Signal Initiator
Target molecule
Signal mediator
Action
Cyclic AMP System
Receptor
Adenylate cyclase
G-protein
Protein kinases
c-AMP
Stimulate (Gs) and inhibit (Gi)
G-Proteins
So-named because they bind GTP, displacing GDP
Work with many receptors
Both Stimulate and inhibit hormone signals
A family of membrane proteins that exist in an inactive(GDP) and an active (GTP) state
GTP is a time-bomb slowly ticking
When GTP is hydrolyzed to GDP, stimulation is stopped
GTP
GDP
GDPGTP
4 ATP
4 cAMP
Cell response
AT
Protein kinase
ADP
PInactive protein
Active protein
hormone
Adenylate cyclase Signaling System
AC
RS
Inhibitor
Ri
Cell membrane (lipid bilayer)
Growth hormone
Extracellular domainof Growth Hormone Receptor
Intracellular
Extracellular
Growth Hormone Receptor
Binding to receptor forces dimerization of receptor
subunits for cross phosphorylation
-OPO3=
=O3PO-
Tyrosines
Challenge to Students• Many of the proteins that you just saw are coded
by genes referred to as “oncogenes”, meaning they are capable of transforming a normal cell into a cancer cell. Src, Ras, ErbB, affect cell growth and differentiation.
• The viral forms of these genes lack regulation, and the mammalian form (proto-oncogenes) are subject to mutation.
• If you want to learn what causes a normal cell to become a cancer cell (malignant transformation), this is a good place to start.
What is Behind the Biochemistry of Cancer?
1. An alteration of genes/proteins involved in:a. Cell proliferation
b. Apoptosis (programmed cell death)
c. Differentiation
2. Acquisition of a phenotype that allows cells to:
a. Proliferate without limitsb. Evade apoptosis
c. Generate its own mitogenic signals
d. Ignore growth inhibitory signalse. Acquire vasculature (angiogenesis) – solid tumors
f. Invade and colonize (metastasize) other tissueLate Stage
Genes Mutated1. ras protein (25% of cancers)
2. p53 tumor suppressor (50% of cancers)
a. controls DNA repair
b. controls apoptosis
3. Tyrosine kinase receptor (HER2/neu)
a. controls ras (overexpression)
We Know1. Biochemical pathways from ras to p53
2. Role of p53 in apoptosis and DNA repair
We Don’t Know1. Molecular circuitry for enhancing secretion of angiogenic factors from cancer cells
2. The regulation of elements controlling the migration and extravastion capabilities of cancer cells
Take HomeTake Home
• Most hormones never penetrate cells
• All hormones have receptors
• Internal responses are initiated by the receptor
• Receptors work with G proteins
• G proteins stimulate protein kinases
• Protein kinases comprise a cell signaling cascade
• G proteins turn off when GTP is hydrolyzed to GDP, canceling the hormone action
• Most hormones never penetrate cells
• All hormones have receptors
• Internal responses are initiated by the receptor
• Receptors work with G proteins
• G proteins stimulate protein kinases
• Protein kinases comprise a cell signaling cascade
• G proteins turn off when GTP is hydrolyzed to GDP, canceling the hormone action
Take Home (Part 2)Take Home (Part 2)
• Some receptors are protein tyrosine kinases
• Kinase activity is initiated by dimerization
• Kinase autophosphorylate receptors
• Phosphotyrosines bind to SH-2 domains
• Activation starts a kinase cascade
• Phosphorylated proteins enter nucleus
• DNA transcription turns on specific genes
• Some receptors are protein tyrosine kinases
• Kinase activity is initiated by dimerization
• Kinase autophosphorylate receptors
• Phosphotyrosines bind to SH-2 domains
• Activation starts a kinase cascade
• Phosphorylated proteins enter nucleus
• DNA transcription turns on specific genes