106

6. Extracellular Messengers
CHEMICAL SIGNALING

• ENDOCRINE SIGNALING
• A hormone synthesized in an endocrine
gland is transported by blood to a target
tissue to induce a response

• PARACRINE SIGNALING
• A messenger synthesized in a tissue
diffuses throughout the same tissue to
induce a response

• AUTOCRINE SIGNALING
A messenger synthesized in a ceil acts
on the cell itself
 107
Chemical Signaling

=> Chemical + traffic signal

Messenger
Receptor

Endocrine

Endocrine Signaling
=> hormone transported
to target tissue by blood

T/SSUB

Paracrine

Paracrine Signaling
=> pair of cryin' eyes
=> messenger
synthesized diffuses
throughout the
same tissue

Autocrine

Autocrine Signaling
=> auto cryin'
=> messenger
synthesized in a
cell acts on the
cell itself
108
6. Extracellular Messengers

NOTES STEROID HORMONES

Cholesterol is the precursor to all steroid
hormones
21-carbon steroids: progesterone,
aldosterone, and Cortisol
19-carbon steroids: androgens,
precursors to estrogens
18-carbon steroids: estrogens
Hydroxybutylation reactions introduce
oxygen functions in steroid hormone
synthesis. Cytochrome P-450 is an
intermediate electron carrier in these
reactions
Dihydrotestosterone (DHT) is more
potent than its prohormone, testosterone

CLASS OF STEROID STIMULATED BY SECRETED BY EXAMPLES

Progestins Luteinizing hormone Corpus luteum, Progesterone

(LH) placenta

Mineralocorticoids ACTH, angiotensin II Adrenal cortex Aldosterone

(zona glomerulosa)

Glucocorticoids ACTH Adrenal cortex Cortisol

(zona fasciculata)

Androgens Luteinizing hormone Leydig cells, adrenal Testosterone

(LH), ACTH cortex (zona reticularis)

Estrogens Follicle-stimulating Ovarian follicle Estradiol

hormone (FSH)

ACTH = adrenocorticotropic hormone

Luteinizing hormone (LH) => left hand
Progesterone => pro jester
Testosterone => test
Mineralocorticoids => minerals = stones
Angiotensin II => tense Angie
Aldosterone => Al's stones
Glucocorticoid => glue
Cortisol => core
Follicle-stimulating hormone (FSH) => fish
Estradiol => Esther Estrogen

• Corticotropin-releasing hormone (CRH)

is released from the hypothalamus and
stimulates the anterior pituitary to
release adrenocorticotropic hormone
(ACTH)
• ACTH stimulates cholesterol desmolase
to increase steroid hormone synthesis in
the adrenal cortex
• Negative feedback control occurs with
Cortisol. Elevated levels of Cortisol inhibit
the secretion of CRH and ACTH

Hypothalamus CRH —»—» Anterior pituitary -»-» ACTH —>—> Adrenal cortex
T T 1
T negative effect T negative effect 1
T T i
<— Cortisol
 109
Steroid Hormones

^HQL^terol^ ACTH

Cholesterol
desmolase

,^~~Dehydroepiandrosterone j
I Pregnenolone i J_ 17-Hydroxypregnenolone X
I -* *"1 r 17a- l — '
pregnant Hvdroxvlase 3f!.Hydroxysteroid 3p-Hydroxysteroid
3P-
dehydrogenase dehydrogenase
Hydroxysteroid
dehydrogenase
\/ \
/ I x—
>(" Androstenedione j
J Progesterone 17-Hydroxyprogesterone
17a-
=> pro jester Hydroxylase

21 p-
21p- Hydroxylase
Hydroxylase
v
Testosterone
/ r 7! I \ f~ 11-Deoxycortisol )
[ 11-Deoxycorticosterone ) V =>test
5a-
11P-
np- Reductase
Hydroxylase
Hydroxylase
cA & FSH
FSH
fish tx©
Ua* J* Cortisol 1 ( Dihydrotestosterone J
Corticosterone => core (DHT)
cord to the stereo ""W Glucocorticoid
Aldosterone => glue

C
synthase
Estradiol
Esther Estrogen

Androgens
/</
M *A> Angiotensin II
Al's stones => tense Angie

Mineralocorticoids
=> mineral = stones
110
6. Extracellular Messengers

NOTES BIOGENIC AMINES

• Biogenic amines include
catecholamines, serotonin
(5-hydroxytryptamine), and histamine
• Biogenic amines are water soluble,
stored within vesicles, and released by
exocytosis
• Synthesized from aromatic amino acids
• Catecholamines include dopamine,
norepinephrine (noradrenaline), and
epinephrine (adrenaline)
Catecholamines => cat call + NH3
Dopamine => dope is mine
o Catecholamines are synthesized
from tyrosine
Tyrosine => tire
o Tyrosine hydroxylase converts
L-tyrosine to L-dopa, which is the
committed step in the pathway
L-Dopa => dopey
o The synthesis of dopamine occurs
in the cytoplasm, while the synthesis
of norepinephrine and epinephrine
occurs in storage granules
o Dopaminergic neurons contain only
tyrosine hydroxylase and dopa
decarboxylase. The adrenal medulla
contains all the enzymes for the
entire pathway
o Monoamine oxidase (MAO) and
catechol-O-methyltransferase
(COMT) are enzymes that inactivate
the catecholamines
MAO => cat's meow
o Dopamine is metabolized to
homovanillic acid (excreted in urine)
o Norepinephrine and epinephrine are
metabolized to vanillylmandelic acid
(excreted in urine)
Vanillylmandelic acid => vanilla
cake and ice cream
• Serotonin (5-hydroxytryptamine; 5-HT)
Serotonin => Sir O'Tonin
o Serotonin is synthesized from
tryptophan
Tryptophan => trip the fan
o Synthesis occurs in the
enterochromaffin cells of neurons
(CNS), lungs, Gl tract, and platelets
Enterochromaffin => chrome fin
o Only MAO inactivates serotonin
• Histamine is released by basophils and
mast cells as an allergic response
o Histamine is synthesized from
histidine
 I l l
Biogenic Amines

Catecholamines
112
6. Extracellular Messengers

NOTES ACETYLCHOLINE
=> a sea
• Acetylcholine is the neurotransmitter at
the neuromuscular junction. This
synapse is between the a-motor neuron
and a skeletal muscle fiber
Skeletal muscle fiber => muscle man
• Role of acetylcholine
1. Acetylcholine is formed by
combining acetyl-CoA and choline
with the enzyme choline
acetyltransferase in the presynaptic
cell (neuron)
2. Acetylcholine is packaged into
synaptic vesicles
3. A voltage-gated calcium channel
opens with membrane
depolarization. Calcium enters the
cell and induces exocytosis
4. Acetylcholine diffuses across the
synaptic cleft to act on receptors in
the postsynaptic membrane (the
muscle fiber)
5. Acetylcholine is degraded by
acetylcholinesterase to acetate and
choline, and the postsynaptic
membrane is repolarized. These
products are taken up by the nerve
terminal to re-form acetylcholine
• Botulinum toxin inhibits acetylcholine
release, leading to flaccid paralysis
Botulinum => robot
• Organophosphates irreversibly inhibit
acetylcholinesterase
Organophosphates => flower
(organic) + P04 (phosphate)
• Curare blocks acetylcholine receptors,
leading to flaccid paralysis
Curare => cure
 113
Acetylcholine

ACh = acetylcholine
P-H = ACh receptor
114
6. Extracellular Messengers

Biogenic amines => NH3

• Biogenic amines: catecholamines
(dopamine, norepinephrine,
epinephrine), serotonin (5-HT)
1. Packaged into synaptic vesicles
2. Calcium induces exocytosis with
membrane depolarization and
opening of calcium channels
3. Sodium-dependent, high-affinity
uptake occurs back into the
presynaptic nerve terminal to
terminate synaptic action
4. The neurotransmitter can be
repackaged into synaptic vesicles or
degraded by monoamine oxidase
(MAO)
MAO => meow
• Cocaine inhibits uptake of dopamine,
norepinephrine, and serotonin
Cocaine => Coke + cane
• Reserpine inhibits storage of
catecholamines and serotonin in vesicles
Reserpine => serpent
• Amphetamines release cytoplasmic
(nonvesicular) dopamine, norepinephrine,
and serotonin
• Other amino acids and peptides act as
neurotransmitters. Glutamate, aspartate,
GABA, glycine (inhibitory), enkephalins,
and substance P are some examples
 1
Biogenic Amines as Neurotransmitters

NH,

NT = neurotransmitter
(biogenic amine)

Monoamine oxidase Reserpine

degrades NT inhibits
MAO => meow vesicular
storage
=> serpent

HT,Neurotransmitters
packaged
Membrane into
depolarization
induces calcium-
dependent exocytosis
Cocaine
^1%®/ 2~7
inhibits
(Channel I- uptake
» Coke + cane

Sodium-dependent,
+s* iy\ K A * - * high-affinity uptake

Receptors

POSTSYNAPTIC CELL
6. Extracellular Messengers

NOTES
L
=> girl gabbing
• GABA is an inhibitory neurotransmitter
1. Glutamate decarboxylase converts
glutamate to GABA
Glutamate => glue
2. GABA is packaged into vesicles and
released by calcium-dependent
exocytosis
3. GABA is taken back up into the nerve
terminals by sodium-dependent,
high-affinity uptake to be stored
again in vesicles or converted
4. GABA transaminase converts
GABA to inactive succinic
semialdehyde
GABA transaminase => GABA train
• Benzodiazepines sensitize GABA-A
receptors to produce a sedative or
anticonvulsant effect
Benzodiazepines => Benz in the pines
 117
y-Aminobutyric acid (GABA)

=> girl gabbing

PRESYNAPTIC CELL

Glutamate

Glutamate
Membrane decarboxylase
depolarization
opens
Succinic
calcium GABA semialdehyde
channels
to induce Storage
exocytosis vesicles GABA transaminase
=> GABA train

^Channel Sodium-dependent,
high-affinity
Exocytosis uptake

SYNAPSE Benzodiazepines
sensitize GABA-A
receptors
=> Benz in
the pines
Receptors

Sedative

GABA is INHIBITORY!

POSTSYNAPTIC CELL
118
6. Extracellular Messengers

NOTES THYROID HORMONES ^ ,

• Thyroid hormones are synthesized only
by the thyroid gland
• Thyroid hormone synthesis is stimulated
by thyroid-stimulating hormone (TSH)
• TSH, released from the anterior pituitary,
stimulates all steps in thyroid hormone
synthesis
Anterior pituitary => ant's pit
1. The iodide pump (trap) located in
the thyroid follicular cells transports
iodide ions (I-) into the follicular cells
Follicular cells => fall lick
2. Thyroglobulin (TG) has tyrosine side
chains incorporated on ribosomes.
Thyroglobulin is secreted into the
lumen of the thyroid follicle
TG has tyrosine side
chains => TG with tires
3. Thyroperoxidase oxidizes I" to l2
(reactive form)
=> peroxide
4. Organification of l 2 also occurs via
thyroperoxidase. Tyrosine side
chains of thyroglobulin react with l2
to form monoiodotyrosine (MIT) and
di-iodotyrosine (DIT)
MIT => one iodo finger
DIT => two iodo fingers
5. Thyroxine (T4) is formed when two
DITs combine
Tri-iodothyronine (T3) is formed
when one MIT combines with one
DIT
6. lodinated thyroglobulin is taken back
into the follicular cells by pinocytosis,
and T3 and T4 are released into the
circulation by lysosomal proteases
7. Residual MIT and DIT are
deiodinated by thyroid deiodinase
and the l2 is reused
8. Thyroxine-binding globulin (TBG)
binds the T3 and T4 in the circulation
=> TBG, T3, T4 holding hands
9. In target tissues, T4 is converted to
T3 or to reverse T3 (rT3)
• T3 is approximately four times stronger
than T„
 119
Thyroid Hormones

TSH stimulates TSH is released from

thyroid hormone synthesis the anterior pituitary
=> ant's pit H

Thyroxine-binding globulin
(TBG) binds T3 and T4
=> holding hands

T4 is converted toT3 or
rT3in target tissues

Lysosomal proteases
Iodide release T3 and T4
pump into circulation K

Follicular cell
=> fall lick

Thyroid
deiodinase
Thyroperoxidase
oxidizes r to l3
=> peroxide
Pinocytosis

<£/ Thyroperoxidase
^ => peroxide

TG secreted .^Organification p
MIT
into ^
lumen f

Monoiodotyrosine (MIT)
=* one iodo finger
Thyroglobulin
Di-iodotyrosine (DIT)
(TG) has tyrosine
=> two iodo fingers
side chains
=> TG with tires
120
6. Extracellular Messengers
EICOSANOIDS
• Eicosanoids are active lipids derived
mainly from arachidonic acid, a
polyunsaturated 20-carbon fatty acid
• Eicosanoids include prostaglandins,
thromboxane, and leukotrienes
• Eicosanoids act as paracrine and
autocrine messengers produced by all
cells except RBCs and lymphocytes
• Arachidonic acid is released from
membrane phosphoglycerides by either
phospholipase A2 or phospholipase C
and diglyceride lipase
• Arachidonic acid leads to two pathways
that produce eicosanoids: the cyclo-
oxygenase pathway and the
lipoxygenase pathway
• The cyclo-oxygenase pathway produces
prostaglandins, prostacyclin, and
thromboxane. The major enzyme is the
prostaglandin synthase complex, which
includes cyclo-oxygenase and
peroxidase
o Prostacyclin (PGI2) is released from
endothelium to prevent thrombus
formation and platelet aggregation
o Thromboxane A2 (TXA2) is released
by aggregating platelets. TXA2
causes vasoconstriction and platelet
aggregation. TXA2 is antagonized by
prostacyclin (PGI2)
o Prostaglandins PGE, and PGI, are
vasodilators and relax smooth
muscle. PGE, maintains a patent
ductus arteriosus in infants with
pulmonary stenosis
o Prostaglandins PGE2 and PGF2o
induce uterine contraction
o PGE2 and TXA2 are also local
mediators of inflammation
• The lipoxygenase pathway produces
leukotrienes HPETE and HETE from
arachidonic acid. The enzyme is
5-lipoxygenase
o Leukotrienes are bronchial and
intestinal smooth muscle constrictors
o Leukotrienes LTC4, LTD4, and LTE4
are responsible for
bronchoconstriction in asthma
o HETEs regulate white blood cells
o Both leukotrienes and HETEs are
involved in inflammation and
hypersensitivity reactions
• Anti-inflammatory drugs are used to
inhibit the synthesis of eicosanoids
o Glucocorticoids inhibit
phospholipase A2 t o reduce the
synthesis of all eicosanoids
o Nonsteroidal anti-inflammatory
drugs (NSAIDs) include aspirin and
ibuprofen. NSAIDs inhibit cyclo-
oxygenase to inhibit prostaglandin
synthesis only
 121
Eicosanoids

Membrane Lipids

Phospholipase A2 Glucocorticoids
inhibit
phospholipase A2
NSAIDs inhibit => glue
cyclo-oxygenase I'M EiCO
=> aspirin THE
Amcwnid

Arachidonic acid
=> spider = arachnid

Lipoxygenase
Cyclo-oxygenase pathway
=> lips
pathway

Thromboxane A2 (TXA2)
aggregates platelets
=> b ox with plates
aggregating

PGI2
antagonizes
TXA2

Prostacyclin (PGI2)
prevents platelet
aggregation
=> cycle punching
plates

Prostaglandins PGE
and PGI relax
smooth muscle

Leukotrienes
constrict bronchial
3rostaglandins PGE2 and PGF2a smooth muscle
nduce uterine contraction
=> pregnant woman
122!
7. Intracellular Messengers
mmam
m
illSi

mi
a

Sm

a S fafa;:;::::

••i
 123
Adrenergic Receptors: a,

(*i receptors located on the following:

Major
neurotransmitter
released is
norepinephrine

triphosphate
Formation
of inositol
1,4,5-trisphosphate
leads to
Constriction of
bladder and Gl
sphincters
124
7. Intracellular Messengers
•mm mm —

i S : - i: : . > i : Si

:
 125
Adrenergic Receptors: a2

V?

Synapse

a2 receptors are on presynaptic

neurons and inhibit adenylate
cyclase, therefore inhibiting
conversion of ATP to cAMP

Found in:

Plate
platelets
126
7. Intracellular Messengers
 127
Adrenergic Receptors: p,

P-i re ceptors
located in
SA and AV
nodes and Produces excitation:
ventricular 1) T heart rate,
muscle 2) t contractility,
3) t conduction velocity

Stimulation of
adenylate cyclase,
causing T conversion P-, s ensitive to
of ATP to cAMP norepinephrine
and epinephrine
128
7. Intracellular Messengers

ss®;; isssil
* 5 -

wfmn.

81 ::f;i
 129
Adrenergic Receptors: p2

p2 causes relaxation:

Activates adenylate cyclase,

causing ATP conversion to cAMP

causes
bronchioles

Relaxation of
bladder
\ muscle /

Relaxation

On Heart
vascular
smooth
muscle
of skeletal
muscle,
causing
dilation
130
7. Intracellular Messengers

NOTES
 131
Cholinergic Receptors: Nicotinic Receptor

=> nicotine cigarette

132
7. Intracellular Messengers
mmm
 133
Cholinergic Receptors: Muscarinic Receptor

=> Mustang car

Excites glands
and smooth

=> muscarinic receptor

134
7. Intracellular Messengers

NOTES
WBIliii
• Hormones that use the cAMP
mechanism of action
o "Adenosine Cyclase Loves Teaming
with Her GTP-Binding protein to Form
cAMP"
• A ACTH (adrenocorticotropic
hormone)
• C -» CRH (corticotropin-
releasing hormone)
• L -> LH (luteinizing hormone)
• T —»TSH (thyroid-stimulating
hormone)
• H -» HCG (human chorionic
gonadotropin)
• G —> Gluc agon
• B P, and P2 r eceptors
• F FSH (follicle-stimulating
hormone)
• c -» Calcitonin
• A —» ADH (V2 receptor)
(antidiuretic hormone or
vasopressin)
• M —» MSH (melanocyte-
stimulating hormone)
• P -» PTH (parathyroid hormone)
• Steps of mechanism
1. Hormone binds to receptor
2. GDP replaced by GTP on G protein
3. Stimulatory G protein activated (or
inhibitory G protein)
4. Stimulatory G protein activates
adenylate cyclase (inhibitory G
protein inhibits adenylate cyclase)
5. Adenylate cyclase converts ATP
ADP
6. cAMP activates protein kinase A
7. Activated protein kinase A
phosphorylates proteins
8. Initiates physiologic effects
 135
Cyclic Adenosine Monophosphate (cAMP)
136
7. Intracellular Messengers
IP3 (INOSITOL 1,4,5-
TRISPHOSPHATE)
MECHANISM
Hormones that activate the IP3
mechanism
o ADH (V, receptor) (antidiuretic
hormone or vasopressin)
o a, receptors
o TRH (thyrotropin-releasing hormone)
o Angiotensin II
o GHRH (growth hormone-releasing
hormone)
o GnRH (gonadotropin-releasing
hormone)
o Oxytocin
Steps in mechanism
1. Hormone bound to receptor
2. G protein activated
3. G protein activates phospholipase C
4. Phospholipase C breaks down
phospholipids
5. Destruction of phospholipids
produces IP3 and diacylglycerol
6. Endoplasmic reticulum (ER)
releases calcium
7. Diacylglycerol + calcium activates
protein kinase C
8. Protein kinase C phosphorylates
proteins
9. Initiates physiologic effects
Diacylglycerol -> arachidonic acid ->
prostaglandins
 137
IP3 (Inositol 1,4,5-Trisphosphate) Mechanism

Hormone
bound to
receptor

3. G protein
activates
phospholipaseC

2.
G protein
activated

Phospholipase
C breaks down
phospholipids

Destruction of
phospholipids
produces
IP, and

6.
Endoplasmic
reticulum (ER)
releases calcium
"Arachnid with acid"
=> arachidonic acid
Diacylglycerol +
calcium activates
protein kinase C

*Diacylglycerol Prostaglandins
=>arachidonic acid Protein 8. 9.
^prostaglandins kinase Protein kinase Initiates
C \\ C phosphorylates physiologic
proteins effects
138
7. Intracellular Messengers
STEROID AND THYROID
HORMONE MECHANISM
• Hormones that utilize mechanism
o Aldosterone
o Progesterone
o Testosterone
o Estrogen
o Glucocorticoids
o Vitamin D
o Thyroid hormone
Steps in mechanism
1. Steroid diffuses across cell
membrane
2. Steroid binds cytoplasmic receptor
3. Steroid binds to nuclear receptor
4. Conformational change of receptor
—> DNA-binding domain revealed
5. DNA reacts with DNA-binding
domain
6. Transcription of mRNA
7. mRNA translation
8. Protein production responsible for
initiating physiologic effects
 139
Steroid and Thyroid Hormone Mechanism

1.
Steroid diffuses across
cell membrane

Steroid binds
cytoplasmic
receptor

Cytoplasmic
receptor

'$V 3-
\\ Steroid binds
to nuclear
DNA-binding receptor
domain on
receptor

Conformational
change of receptor -»
DNA-binding domain
revealed
DNA reacts
with DNA-
binding domain

7.
mRNA
translation Transcription
, ofmRNA

8.
Protein
production
responsible for
initiating
physiologic
effects
140
7. Intracellular Messengers

NOTES
CALCIUM-CALMODULIN
MECHANISM
• Steps in mechanism
1. Hormone bound to receptor
2. G protein activates cell membrane
calcium channel
3. G protein activates release of calcium
from endoplasmic reticulum (ER)
4. Increase in intracellular calcium
concentration
5. Calcium binds to calmodulin
6. Calmodulin initiates physiologic
effects
 141
Calcium-Calmodulin Mechanism

Hormone
bound to
receptor G protein activates
membrane calcium channel
Calcium
channel
Receptor
Hormone

Protein

>\asmic
cv>\um

Increase in
intracellular
calcium
concentration

Calcium
binds to
calmodulin

6- Calmodulin