HORMONE ACTION AND SIGNAL

TRANSDUCTION
DR. IRENE CATAMBING-DAMPIL, MD, FPCP, FPSEDM
 HORMONES AND HOMEOSTASIS

The homeostatic adaptations an organism makes to a constantly changing

environment are in large part accomplished through alterations of the activity
and amount of proteins.

Hormones provide a major means of facilitating these changes.

 HORMONES AND HOMEOSTASIS

A hormone-receptor interaction results

in generation of an intracellular signal
that can:

1)regulate the activity of a select set

of genes

2) affect the activity of certain proteins

Excessive, deficient, or inappropriate

production and release of hormones
and of these other regulatory
molecules are major causes of disease.
TARGET CELL CONCEPT
SPECIFICITY AND SELECTIVITY OF RECEPTORS
HORMONAL INVOLVEMENT IN RESPONSES TO STIMULI
HYPOTHYROIDISM (DECREASING FREE HORMONES)
 SIGNAL GENERATION

• hormones diffuse through

the plasma membrane or
nucleus

• activation reaction occurs

with the hormone-receptor
complex

• activated receptor binds to

HRE (or GRE)

• binding leads to gene

transcription
hormone

transcription regulators

SIGNAL GENERATION
GROUP 1 HORMONES
Many hormones can act at any
step of this information
pathway to control a specific
gene expression and
ultimately elicit a biological
response
 ACTH
increase in cholesterol substrate for steroidgenic enzymes
By selectively affecting gene transcription and the consequent
increase transcription of enzymes

production of appropriate target mRNAs, the amounts of specific

proteins are changed and metabolic processes are influenced.

The influence of each of these hormones is quite specific;

generally, a given hormone directly affects <1% of the genes,
mRNA, or proteins in a target cell; sometimes only a few are
affected.
SIGNAL GENERATION: MEMBRANE RECEPTORS AND
INTRA-CELLULAR SIGNALING
GROUP 2 HORMONES
GROUP 2 HORMONES

• water soluble

• no transport proteins

• short half life

• generates intracellular signals

(second messengers)

• cAMP

• cGMP

• Ca+

• phosphoinositides
G-PROTEIN COUPLED RECEPTORS (GPCR)
7 hydrophobic plasma membrane spanning domains
CAMP
 CAMP

• first intra-cellular signal

second messenger
identified in mammals
 PROTEIN KINASES
cAMP binds to a protein kinase
called protein kinase A (PKA),
a heterotetrameric molecule
consisting of two regulatory
subunits (R) that inhibit the
activity of the two catalytic
subunits (C) when bound as a
tetrameric complex.
 A KINASE ANCHORING PROTEINS

• AKAPs serve as scaffolds,

which localize PKA near to
substrates

• focuses PKA activity toward

physiological substrates and
facilitating spatiotemporal
biological regulation

• allows for common, shared

proteins to elicit specific
physiological responses.

• facilitates signaling
dynamics and specificity
 PHOSPHOPROTEINS

• The effects of cAMP on gene

transcription are mediated by
CREB,

• . CREB binds to a cAMP

responsive DNA enhancer
element (CRE)

• When phosphorylated by PKA,

CREB binds the coactivator
CREB-binding protein CBP/
p300 and produces a potent
transcription activator
•
PHOSPHODIESTERASES
Actions caused by hormones that increase cAMP concen-
tration can be terminated in a number of ways, including the
hydrolysis of cAMP to 5ʹ′-AMP by phosphodiesterases.

these hydrolytic enzymes ensures a rapid turnover of the

signal (cAMP) and a rapid termination of the biologic process
once the hormonal stimulus is removed.

There are at least 11 known members of the

phosphodiesterase family of enzymes.

These are subject to regulation by their substrates, cAMP and

cGMP; by hormones; and by intracellular messengers such as
calcium, probably acting through calmodulin.
CGMP

• acts as an intracellular
signal

• made from GTP by the

enzyme guanylyl cyclase,
which exists in soluble and
membrane-bound forms.

• cause smooth muscle

relaxation and are potent
vasodilators
•
CALCIUM
CALCIUM AS AN INTRA-
CELLULAR SECOND MESSENGER

The extracellular Ca2+

concentration is ∼5 mmol/L and is
very rigidly controlled.

The intracellular concentration of

free or ionized calcium (Ca2+) is
very low: 0.05 to 10 μmol/L.
INTRA CELLULAR CALCIUM

• Na/Ca+ exchanger - high

capacity, low affinity

• Ca+/proton ATPase - high

affinity, low capacity

• Ca2+ATPase pump - from

cytosol to ER
CYTOSOL CALCIUM
REGULATION
• (1) Certain hormones, by binding to
receptors that are them- selves Ca
2+

channels, enhance membrane

permeability to Ca , and thereby
2+

increase Ca influx.
2+

• (2) Hormones indirectly promote Ca 2+

influx by modulating the membrane

potential at the plasma membrane.
Membrane depolarization opens
volt- age-gated Ca channels and
2+

allows for Ca influx.

2+

• (3) Ca can be mobilized from the

2+

endoplasmic reticulum, and possibly

from mitochondrial pools.
2+
 CALMODULIN

• calcium dependent regulatory

protein

• homologous to muscle troponin

• has 4 Ca++ binding sites, when

bound or at full occupancy leads to
conformational change which
allows calcium and ion regulation

• involved in regulation of kinases

and enzymes of nucleotide
degeneration and regeneration

• regulates other intracellular activity

elements: cell motility, mitosis,
granule release, endocytosis
CALMODULIN AT WORK
CALCIUM IS A MEDIATOR OF
HORMONE ACTION

• A role for Ca in hormone action is

2+

suggested by the observa- tions

that the effect of many hormones is

• (1) blunted by Ca -free media or

2+

when intracellular calcium is

depleted;

• (2) can be mimicked by agents that

increase cytosolic Ca , such as the
2+

Ca ion- ophore A23187; and

2+

• (3) influences cellular calcium flux.

Again, the regulation of glycogen
metabolism in liver (by vasopressin
and β-adrenergic catecholamines
•
 PHOSPHATIDYLINOSITIDE AFFECTS
CALCIUM DEPENDENT HORMONE ACTION

• provides communication
from hormone receptor in
the plasma membrane to
intracellular Ca++ stores

• activates calmodulin
• The activated protein kinase C can
• phosphorylate specific substrates,
• alter physiologic processes.
• the Ca2+-calmodulin complex can activate specific kinases.
• modify substrates and thereby alter physiologic responses.
SOME HORMONES ACT THROUGH A
VARIETY OF PROTEIN KINASE
CASCADE
• Single protein kinases such as PKA, PKC, and Ca - calmodulin (CaM)-kinases,
2+

which result in the phosphorylation of serine and threonine residues in target

proteins, play a very important role in hormone action.

• The insulin and IGF-I receptors also contain intrinsic ligand-activated tyrosine
kinase activity.

• Several receptors—generally those involved in binding ligands involved in

growth control, differentiation, and the inflamma- tory response—either have
intrinsic tyrosine kinase activity or are associated with proteins that are tyrosine
kinases.

• . A third distinguishing feature is that the ligand-receptor interaction that results

in a tyrosine phosphorylation event initiates a cascade that involve several
protein kinases
PROTEIN
KINASE AT
WORK
ACTION OF THE SECOND
MESSENGER
ACTION OF THE SECOND
MESSENGER
ACTION OF THE SECOND
MESSENGER
INSULIN SIGNALLING PATHWAY
 JAK-STAT
PATHWAY

Some hormones, such as growth hormone, prolactin,

erythropoietin, and the cytokines, initiate their action
by activating a tyrosine kinase, but this activity is not
an integral part of the hormone receptor.
JAK - association proteins
STAT - Signal transducers and activators of
transcription (cytosolic proteins)
 NUCLEAR
FACTOR KB
PATHWAY
affected by glucocorticoids

translocates to the nucleus

capable of activating pro

inflammatory responses
HORMONES CAN INFLUENCE SPECIFIC
BIOLOGIC ACTIVITIES BY MODULATING
TRANSCRIPTION

• 1) actively transcribed genes are in

• (4) Alternatively, other hormone-
regions of “open” chromatin
generated signals can modify the
(experimentally defined as relative
location, amount, or activ- ity of
suscep- tibility to the enzyme transcription factors and thereby
DNase I), which allows for the influence binding to the regulatory
access of transcription factors to or response element.
DNA.
• (5) Members of a large superfamily
• (2) Genes have regulatory regions, of nuclear receptors act with—or in a
and transcription factors bind to manner analogous to—the hormone
these to modulate the frequency of receptors described above.
transcription initiation.
• (6) These nuclear receptors interact
• (3) The hormone- receptor complex with another large group of
can be one of these transcription coregulatory molecules to effect
factors. The DNA sequence to changes in the transcription of
which this binds is called a HRE. specific genes.
•

•
HORMONE
RESPONSE
TRANSCRIPTION
UNIT
is an assembly of DNA elements and
complementary, cognate DNA-bound
proteins that interact, through protein–
protein interactions, with a number of
coactivator or corepressor molecules.
An essential component is the hormone
response element that binds the ligand (!)-
bound receptor (R). Also important are the
accessory factor elements (AFEs) with
bound transcription factors.
NUCLEAR RECEPTOR PROTEINS
SUPERFAMILY
THANK YOU