CHEMICAL SIGNAL:

HORMONE 1

BIOSIGNALING

(WEEK 2)
 WHAT IS HORMONE?

Chemical signal that can affect the

process (metabolism, enzyme activity,
gene expression, etc) mechanisms within
the target cell or tissue
 GENERAL MECHANISMS OF HORMONAL PROCESS
Synthesis Location and regulation of
synthesis
Mechanism of synthesis
Secretion
Transport Water soluble
Detection detection, response & termination systems
Response Lipid soluble
Termination

Various hormones Blood

stream

Various endocryne cells

A B C
A B C

Various target cells

 DETECTION OF HORMONE SIGNALING SYSTEMS

Lipid soluble hormone Small hydrophobic signaling molecule

Non polar
Pass through the membrane cell Carrier protein
Receptor within the cell (Intracellular receptor)
Requires carrier molecule
Affect gene expression
Affect the quantity of active protein Intracellular receptor

Water soluble hormone Plasma membrane

Polar Cell-surface
Can not pass through the membrane cell receptor
Receptor on the cell surface
(G protein-linked or tyrosine kinase receptor)
+/- second messenger Hydrophilic
Affect the activity of enzyme or active protein signaling
Affect the quality of the enzyme or active protein molecule
 The Reception and Transduction of Signals

Glucagon G-protein-linked Receptor

Adenylate cyclase
+ Signal

a a a a
GTP GTP
-GDP b g GDP b g
+GTP GDP

G protein
A Glycogen breakdown

The third group:

Ion-channel-linked Receptor Insulin Enzyme-linked Receptor
The fourth group: a
+ Signal
Steroid Receptor

Glycogen Activation P kinase P b

P P
Synthase
Protein
active Phosphatase P P
Glycogen
Synthase Glycogen SH2
domain
 GENERAL TYPE OF EUKARYOTIC RECEPTORS

Ion channel-link receptor

Receptor enzymes

Membrane proteins that act through G proteins (serpentine receptor)

Nuclear proteins that bind steroids and act as transcription factors

(steroid/nuclear receptor)

Membrane proteins that attract and activate soluble protein kinases

Adhesion receptors that carry information between the extracellular matrix

and the cytoskeleton.

 BASIC SIGNALING MECHANISMS
1. Gated ion channels of the plasma membrane that open and close (hence the term gating)
in response to the binding of chemical ligands or changes in transmembrane potential.
These are the simplest signal transducers. The acetylcholine receptor ion channel is an
example of this mechanism
2. Receptor enzymes, plasma membrane receptors that are also enzymes. When one of these
receptors is activated by its extracellular ligand, it catalyzes the production of an
intracellular second messenger. An example is the insulin receptor
3. Receptor proteins (serpentine receptors) that indirectly activate (through GTP-binding
proteins, or G proteins) enzymes that generate intracellular second messengers. This is
illustrated by the -adrenergic receptor system that detects epinephrine (adrenaline)
4. Nuclear receptors (steroid receptors) that, when bound to their specific ligand (such as the
hormone estrogen), alter the rate at which specific genes are transcribed and translated into
cellular proteins. Because steroid hormones function through mechanisms intimately related
to the regulation of gene expression
5. Receptors that lack enzymatic activity but attract and activate cytoplasmic enzymes that act
on downstream proteins, either by directly converting them to gene-regulating proteins or
by activating a cascade of enzymes that finally activates a gene regulator. The JAK-STAT
system exemplifies the first mechanism ; and the TLR4 (Toll) signaling system in humans,
the second
6. Receptors (adhesion receptors) that interact with macromolecular components of the
extracellular matrix (such as collagen) and convey to the cytoskeletal system instructions on
cell migration or adherence to the matrix. Integrins illustrate this general type of
transduction mechanism.
 EUKARYOTIC GENERAL TYPES OF SIGNALING MECHANISMS
Serpentine receptor Receptor with no intrinsic
External ligand binding to receptor enzyme activity
(R) activate an intracellular GTP- Interact with cytosolic protein
binding protein (G), which regulates kinase, which activates a gene-
an enzyme (Enz) that generates an regulating protein (directly or
intracellular second messenger (X) througha cascade of protein
kinase), changing gene
expression

Receptor enzyme
Ligand binding to extracellular Adhesion
Gated ion domain stimulates enzyme activity receptor
channel in intracellular domain Binds
Opens or molecules in
closes in extracellular
response to matrix,
concentration changes
of signal Steroid/nuclear receptor conformation,
ligand (S) or Steroid binding to a thus altering
membrane nuclear receptor protein its interaction
potential allows the receptor to with
regulate the expression of cytoskeleton.
Nelson & Cox specific genes.
 TWO GENERAL MECHANISMS OF HORMONE ACTION
The peptide and amine hormones are faster acting than steroid and thyroid hormones
 DETECTION OF LIPID SOLUBLE HORMONE BY INTRACELLULAR RECEPTOR

Non polar
Pass through the membrane cell
Receptor within the cell (Intracellular receptor) Steroid hormone
Requires carrier molecule molecules enter the cell
Affect gene expression Receptor
Affect the quantity of active protein protein

Hormone-receptor complexes

Cytoplasm Nucleus

DNA binding domain

inhibitory protein complex COOH of various hormones
transcription Hormone
activating domain -binding
H 2N site
Hinge region Cortisol receptor
DNA binding domain Estrogen receptor
steroid
hormone Progesterone receptor
RNA Vitamine D receptor
polymerase DNA-binding site exposed
Thyroid hormone receptor
H2 N COOH
Retinoic acid receptor
 GENERAL MECHANISM BY WHICH STEROID AND THYROID HORMONES,
RETINOIDS, AND VITAMINE D REGULATE GENE EXPRESSION
Serum binding protein with bound hormone
H
Plasma membrane
1

Rec Nucleus
2

Altered cell function RNA polymerase

HRE Gene

Transcription 3
New protein mRNA
4

Translation on ribosomes
 THE MAJOR FAMILIES OF TRIMERIC G PROTEINS
Family Some Functions Modified by
Family Subunit bacterial toxins
members
I Gs s Activates adenyl cyclase Cholera activates
Activates Ca2+ channels Cholera activates
Gofl ofl Activates adenyl cyclase in
oflactory sensory neurons
II Gi i Inhibits adenyl cyclase Pertusis activates
Activates K+ channels
Go o Activates Ca2+ channels Pertusis inhibits
Inactivate K+ channels
Activate phospholipase C-
Gt Activates cGP Cholera activates
t
(transducin) phosphodiesterase in and pertusis
vertebrate rod photoreceptors inhibits

III Gq q by aaActivate phospholipase No effect

Families are determined sequence relatedness C-
of the subunit.
Only selected examples are shown.
About 20 subunits and at least 4 subunits and 7 subunits have been
described in mammals
 DETECTION OF WATER SOLUBLE HORMONE BY G PROTEIN-LINKED RECEPTOR

G-PROTEIN-LINKED RECEPTOR
G protein G protein
PLC Adenylate cyclase
IP3 - DAG (2nd messenger) cAMP (2nd messenger)
PKC PKA
Other proteins Other proteins
Hormone Hormone Activated adenylat cyclase
Phospholipase C Extracellular
space
Receptor Receptor

DAG
PI PIP2 Cytosol
IP3
DAG cAMP
2ATP 2ADP IP3
PKC PKA
PI PIP2 Other proteins
Cellular responses ( vary with cell type)
HORMONE UTILIZING G-PROTEIN-LINKED RECEPTOR TO INCREASE cAMP
 SIGNAL-SIMULATION/INHIBITION BY G PROTEINION

G-LINKED PROTEIN RECEPTORS

Simulatory protein (Gs) Inhibitory protein (Gi)

Epinephrine Norepinephrine
-adrenergic 2-adrenergic
receptor (stimulates Adenylate cyclase receptor (inhibites
cAMP synthesis) cAMP synthesis)

GDP
Gs GTP GDP
GTP Stimulates GDP
Gi
Gs protein GDP cAMP
synthesis Gi protein
exchange binds with dissociates
ATP Gs cAMP
cAMP synthesis is
inhibited
Some signals that use cAMP as second messenger
Arrestin uncouples the serpentine receptor from
its G protein and brings together the three
enzymes of the MAPK cascade. The effect is
that one stimulus triggers two distinct response
pathways: the path activated by the G protein
and the MAPK cascade.
Some enzymes and other proteins regulated by c-AMP dependent phosphorylation (by
PKA)
 THE EFFECT OF EPINEPHRINE HORMONE

Epinephrine receptor
Epinephrine Plasma membrane Extracellular space

Activated Cytosol
G protein adenylate cyclase
ATP cAMP (2nd messenger)
Active glycogen synthase
Inactive protein kinase
Active protein kinase Inactive glycogen
(phosphorylated)
Inactive phosphorylase kinase synthase
Active (phosphorylated) phosphorylase kinase

Inactive glycogen phosphorylase

Active (phosphorylated) glycogen phosphorylase

Glycogen
Glucose phosphate Glucose
Hypothalamic regulation of food intake and energy expenditure
ACTIVATION OF A-KINASE BY cAMP
ACTIVATION OF PHOSPHORYLASE KINASE BY A-KINASE
 GP kinase Phosphatase

GP b
GP kinase P

GP a
Glycogen synthase
Glucagon

Glycogen
Glycogen synthase P
A PKA
Protein phosphatase-1

Protein phosphatase-1 P

Protein phosphatase inhibitor-1

active Protein phosphatase inhibitor-1 P

inactive
 SIGNAL AMPLIFICATION
One molecule of signaling ligand Receptor protein

Each activated receptor protein may

activate many molecules of Gs
protein, each of which liberates
an subunit that can activate subunit of Gs protein
an adenylyl cyclase molecule Activated
for a prolonged period adenylyl cyclase

Each activated adenylyl cyclase

molecule generates many
cAMP molecules
cAMP molecules
activate A-kinase

Each A-kinase molecule can

phosphorylate and thereby activate
many copies of enzyme X

Each copy of enzyme X

produces many molecules
of product
ACTIVATION OF PHOSPHATASE INHIBITOR BY A-KINASE
 cAMP Controls Activity of Protein Kinase A

Regulatory A
A Active kinase
subunits A cAMP
A
A C
R C R
A
A
R C Catalytic
R C
A
subunits

Nucleus CREB CREB=cAMP

respon elemen
binding protein (at
Activation
P C somatostatin even)

Gene
CREB expression
DNA ON
DAG & IP3 (2nd MESSENGER)
DAG & IP3 (2nd MESSENGER)