• Hormones are chemical messengers synthesized by


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  • FileName: Mechanisms of hormone action.pdf [read-online]
    • Abstract: Hormones are chemical messengers synthesized byorganisms that initiate biological responses by bindingMechanisms of hormone action with high affinity and specificity to target cell receptors

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Hormones are chemical messengers synthesized by
organisms that initiate biological responses by binding
Mechanisms of hormone action with high affinity and specificity to target cell receptors
within the same individual
Endogenous substance
High affinity and specificity of binding to specific
receptors on target cells
Initiates biological response
Function of hormones Life of a hormone
HOMEOSTASIS
Reproduction
Growth and development
Maintenance of internal environment
Production, utilization and storage of energy
Hormone transport
protein
Chemical nature
of hormones Amino acid derivatives
Derivatives of tyrosine
Catecholamines (epinephrine, dopamine)
Thyroid hormones (dipeptides)
Tryptophan derivative
Can be divided into 3 Melatonin
groups
Amino acid derivatives
Peptide hormones
Lipid derivatives
1
Peptide hormones 2 classes of lipid derived hormones
Glycoproteins from anterior pituitary Steroid hormones:
thyroid-stimulating hormone (TSH) derived from cholesterol
luteinizing hormone (LH) 2 groups
follicle-stimulating hormone (FSH) with the intact steroid ring (adrenal and gonadal
Peptides and small proteins steroids)
Digestive with the steroid ring cleaved (metabolites of vit D)
tract hormones Eicosanoids:
Pituitary hormones derived from
Pancreatic hormones arachidonic acid
Catecholamines Synthesis of catecholamines
Molecules with catechol group Synthesized in cytosol
Hormonal regulators Packaged in vesicles and
Dopamine in hypothalamus exocytosed
inhibits prolactin secretion Water soluble, do not need
Epinephrine (adrenaline) – stress transport proteins
reaction Work from the outside from
Synthesized from aa phenylalanine the cell (bind to surface
or tyrosine in enzymatic reactions receptors)
Synthesis of melatonin (indoleamine) Peptide hormone synthesis
Tryptophan to serotonin Synthesized on the ribosomes attached to rough ER
NAT (N-acetyltransferase) All of them have ER targeting sequence on the N-
is activated only in the dark terminus (signal peptide)
Works on surface Synthesized as prohormones
receptors Inactive molecules converted to active hormones in
ER and Golgi, sometimes after secretion
Exocytosed from the cell
Work from the outside from the cell (bind to surface
receptors)
2
Cell biology vs. endocrinology
Splice variants Preprohormone – full sequence of the peptide
Alternative processing of mRNA can result in splice Prohormone – peptide minus signal sequence
variants of the same hormone Can (and usually does) undergoes additional proteolytic
Availability of transcription factors can affect hormone cleavage in Golgi
production Hormone convertase
Hormone – biologically
active product
Posttranslational processing Posttranslational processing
Signal peptide removal Clevage (Golgi)
Folding (ER) Sometimes multiple copies or even different
Formation of disulfide bonds hormones are produced from the same prehormone
Glycosylation (ER)
ProTRH 6 repeats in humans
5 repeats in rats
Peptide homology Peptide homology
Neurohypophyseal hormones Glycoproteins of anterior pituitary
Alpha subunit identical in all 3 TSH, LH and FSH
3
Shape matters Peptide hormone transport
Usually water soluble
Transported in plasma - require no specific carrier
mechanisms
Insulin and IGF (insulin like growth factor), a “real”
growth hormone
Signaling process Hormone receptors
Recognition of signal Molecules within or on the surface of target cells that bind
Receptors hormones with high affinity and specificity and thereby
Transduction initiate and mediate biological responses
Change of external signal into intracellular message Hormones will only produce the response in cells that
express the receptors for this particular hormone (target
Effect cells)
Modification of cell behavior ONLY target cells
respond to hormone
Cells that do not have
receptors for the hormone
“ignore” the hormone
Properties of the hormone-receptor
interactions Peptide and amine receptors
Tissue specificity - each Surface receptors a.k.a transmembrane receptors
organ has a unique set Peptides and amines cannot cross the membrane
of hormone receptors When activated, a receptor on the surface “passes” the
signal to intracellular second messengers or directly to
cellular effectors to produce biological response
4
Many families of cell surface receptors G protein coupled receptors
Based on homology and signaling strategy Use G-proteins as molecular switch to turn on enzymes
The same ligand can bind to two or more different producing intracellular second messengers
families!!!
Multiple splice variants (β1 and β2 adrenergic receptors)
can be tissue specific
Molecular properties of G protein coupled
G protein coupled receptors = GPCR receptors
Ligand binding to the receptor activates a signal A.k.a. serpentine receptors
transduction cascade that comprises Seven transmembrane regions of 22-24 hydrophobic
G protein – molecular switch residues
Enzyme that produces second messengers N-terminus faces outside (ligand binding domain)
Second messengers C-terminus faces cytosol
Target protein - effector A cytosolic loop between
But not necessary all steps are involved!!!! helices 5 and 6 is the place
for interaction with
G protein
G proteins G protein cycle
Membrane bound heterotrimeric proteins consisting of 3 When G protein is inactive it is bound to GDP and exists
subunits α, β, γ as a trimer
Coupled to surface receptors The exchange of GDP for GTP activates G protein
Molecular switches G protein dissociates into two subunits: α and βγ dimer
Use the exchange and hydrolysis of nucleotides GTP is bound to α subunit
(GTP/GDP) to transduce the signal from the surface α Subunit has an intrinsic GTPase activity and hydrolyses
receptors to intracellular effectors GTP to GDP
This process terminates the signal
α and βγ reassociate
5
Amplification of signal by second
What the G proteins can do? messengers
Activate enzymes to produce second messengers
Activate transcription factors
Modulate ion channels, pumps and exchangers
Affect cytoskeleton
Modulate enzymes
Adrenaline signaling
Differential regulation of adenylate Regulation of transcription by cAMP
cyclase kinase
CREB needs to be
Activated by Gs phosphorylated at
Inhibited by Gi serine 133
Only genes that have CRE sequence Activated CREB binds to CRE
are activated by those receptors sequence and stimulates
transcription
CREB links cAMP signals to transcription Second messengers
Only genes that have CRE sequence in front of cAMP is not the only second messenger initiated
them are activated by these receptors by GPCRs
CREB needs to be phosphorylated at serine 133 IP3 (inositol 1,4,5 – trisphosphate) and DAG
Interacts with a co-activator CBP/P300 (diacylglycerol), are the second messengers for G
Activated CREB binds to CRE sequence proteins from the Gq family
CBP/P300 links CREB to transcription factors They are made by phospholipase C (PLC) that breaks
phoshatidylinositol 4,5 bisphosphate (PIP2) to IP3
and stimulates transcription and DAG
Several other second messenger are derived from
membrane lipids
6
PIP2 breakdown IP3 as a second messenger
IP3 increases intracellular calcium levels via the release
from intracellular stores
DAG activates protein kinase C (PKC)
Calcium is also intracellular second
messenger Protein kinase C (PKC) signaling
Regulation of hormone Serine/threonine kinase
secretion Activated by DAG
Regulation of transcription Phosphorylates various cellular effectors
through Ca- calmodulin Activates transcription factors AP-1 (c-fos and c-jun are
kinase both protooncogenes)
Other lipid
messengers Ceramide signaling
Product of sphingomyelin cycle
Sphingomyelins do not have glycerol backbone
Second messenger in TNF-α signaling and stimulation of
apoptosis
Increase in prostaglandin biosynthesis
Activation of transcription factor NF κb
7
Catalytic receptors with intrinsic
enzymatic activity Receptor tyrosine kinases
Ligand binding causes activation of enzymatic activity of Ligand binding causes dimerization of the receptor
the receptor (receptor itself is an enzyme) This activates enzymatic activity of kinase domain and
Tyrosine kinase phosphorylation of the
Guanylyl cyclase other subunit
Phosphatase Phosphorylated tyrosine
Modification of cellular activity is recognized by molecules
with SH2 domain that will
propagate the signal to
other cellular effectors
RTKs Signaling by RTK
Most RTK are monomers when not Activation of enzymes
crosslinked by ligands Activation of Mitogen Activated Protein Kinase pathways
Insulin receptor stays as a dimer but (MAPK pathways)
ligand binding is necessary for
phosphorylation
How do RTKs activate MAPK pathways and
Enzymes activated by RTK affect transcription?
Phosphotyrosine residues on the kinase interact with
adapter proteins
Transmit a signal to Ras, a monomeric G protein
(molecular switch)
Ras passes the signal to downstream components
Most often - Mitogen Activated Protein Kinase pathways
(MAPK pathways)
8
MAP kinase regulates the activity of
transcription factors Signaling strategies
Receptors that are linked to cytoplasmic enzymes
Cytokine receptors (tyrosine kinase-linked)
Have the capacity to activate cytosolic tyrosine kinases
Receptor itself lacks kinase activity
Activated kinase
phosphorylates
cellular substrates
Receptors that activate intracellular
Tyrosine kinase-linked receptors tyrosine kinases
Have the capacity to activate cytosolic tyrosine kinases
Ligand binding causes dimerization of the receptor
Activation of cytosolic tyrosine kinase
Receptor itself lacks kinase activity
Activated kinase phosphorylates cellular substrates –
second messengers
Signaling by members of the cytokine
Tyrosine kinase-linked receptors receptor family
Signal to nucleus through the JAK-STAT pathway (signal
transducers and activators of transcription)
9
Ion channel receptors Termination of signaling
Ligand gated ion channels Binding a ligand activates the endocytosis of the
Binding of a ligand changes the conformation of the receptors
receptor and opens channel pore In endosomes ligand
Ions move through the pore dissociates from the receptor
Results in changes of the cell excitability based on the pH gradient
Receptors got recycled
back to the membrane
Steroid hormones
Cellular mechanisms of steroid Synthesized from cholesterol in enzymatic reactions in
hormone action cytosol
Lipid soluble
Bind to intracellular receptors
Synthesis of steroid hormones Steroid hormone transport
Will be discussed later when we talk about adrenals Lipid soluble hormones require transport proteins
albumin and transthyretin (prealbumin)
specific transport molecules (thyroxine-binding
globulin)
only unbound hormone can enter the cell !!!
Steroid and thyroid hormones are 99% attached to
special transport proteins
10
Intracellular receptors Structure of nuclear receptors
Receptors for hormones that are able to enter the cell Superfamily of ligand-activated transcription factors
Ligand activated transcription factors Bind to specific DNA sequences as dimers
Localized in nucleus or cytoplasm Similar structure and high homology
Two highly conserved regions
Domain structure of nuclear receptors Mechanism of action of nuclear receptors
In the absence of
hormone the DNA binding
domain is bound to
chaperones (mostly hsp
family)
Binding of a hormone
causes dissociation of hsp
from a receptor and
exposure of DNA binding
domain
Highest homology region
Hormones that bind to intracellular Hormones that bind to intracellular
receptors receptors
All hormones that can cross the membrane
Small hydrophobic molecules
Steroid hormones
Thyroid hormones
1,25-dihydroxycholecalciferol
Retinoic acid
11
Steroid hormone action Lipid soluble hormones effects
Induce transcription and translation
Alter transcription of specific genes
Exert mostly long term effects - growth and
differentiation, new protein synthesis
http://www.maxanim.com/biochemistry/Steroid%20H
ormone/Steroid%20Hormone.swf
Regulation of gene expression by
Regulation of gene transcription homodimer receptors
When not bound to the hormone receptors stay bound Recruitment of a co-activator complex
to chaperones (mostly hsp family) Stabilization of preinitiation complex at TATA box
Binding of a hormone causes dissociation of hsp from a Binding of TFIIB
receptor and eexposure of zinc fingers Binding of
Activated receptors bind to DNA polymerase
Interact predominantly with specific genomic sequences
- hormone responsive elements (HRE)
Localized in the 5’ flanking regions of target genes
Regulation of gene expression by Regulation of gene expression by
heterodimer receptors cytoplasmic receptors
Glucocorticoid receptors are localized in the cytoplams
In the absence of hormone cytoplasmic receptor is
bound to hsp90
Ligand binding displaces hsp90 complex
Receptor – ligand complex translocates to the nucleus
and binds to Hormone Response Element on DNA
12
Regulation of gene expression by
glucocorticoid receptor
Eicosanoids
Derivatives of arachidonic acid
2 groups – prostaglandins and leukotrienes
Prostaglandins are produced by COX enzyme (Cox
inhibitors are NSID)
Important in coordinating tissue responses to injury or
disease
Are important paracrine factors
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