Mechanism of Hormone Action

Dr. Tapan Kr. Dutta

Panskura Banamali College
 What is a Hormone?
Hormones are long-range chemical messengers
secreted into the bloodstream by endocrine (ductless)
glands in response to an appropriate signal, and
carried in the blood to other sites in the body where
they exert their effects on target cells some distance
from their site of release. Hormones generally
produce their effects by altering intracellular protein
activity.
Hormones are classified into three categories based
on their structure:
 Types of Hormones
Peptides: Comprise most hormones, including
those secreted by the hypothalamus, anterior
and posterior pituitary, pancreas and parathyroid.
Amines: Derived from the amino acid, tyrosine,
and include the hormones secreted by the
thyroid gland, and adrenal medulla.
Adrenomedullary hormones are called
catecholamines.
Steroids: Neutral lipids derived from
cholesterol; include hormones secreted by the
adrenal cortex, ovaries and testes. Steroid and
thyroid hormones are lipid soluble (lipophilic).
 Cellular Mechanism of
Hormone Action
Lipid-soluble hormones
Steroid hormones
Androgens, estrogens, progestins,
glucocorticoids, mineralocorticoids, and
thyroid hormones
Diffuse across the plasma membrane
Bind to cytoplasmic or nuclear receptors
Activate
RNA polymerase
DNA transcription and translation
 Hormone Receptors

Allhormones act through

receptors

Cells that contain receptors

are targets
 Hormone Receptors
Hormones regulate specific target
tissues.
How are target tissues selected by
specific hormones?
Determined through receptors on target cells
that provide the specificity for hormone-cell
interactions
Receptors may be located in the cell
membrane, cytoplasm, or nucleus.
Principles of Receptor Binding
1) Hormone specificity
Receptors interact with (bind) specific
hormones
Hormones have a primary receptor, but
may interact with less affinity with other
receptors. Examples:
Progesterone will bind androgen receptors
Aldosterone will bind glucocorticoid receptors
Testosterone will bind estrogen and progestin
receptors

2) High affinity
Receptor affinity is related to
concentration of hormone.
Principles of Receptor Binding
3) Tissue Specificity
Target tissues containing receptors
respond specifically to the hormone
(ligand) that binds the receptor. (At
physiological concentrations)
Some non-specific binding may occur to
other tissues, but this binding is of low
affinity with no hormonal or tissue
specificity.
Principles of Receptor Binding
4) Saturable
Usually one specific binding site per molecule
Should be a finite number of receptors

5) Reversibility
Hormone binding must be reversible.
The on/off rate is dependent on binding affinity

[H] + [R] [HR] Effect

 Number of Receptors

Number of receptors is not static.

Numbers change with physiological

conditions: development,
differentiation, stimulation or inhibition.
 Plasma Membrane Receptors
Spare receptors on the cell surface
Usually more receptors on the plasma
membrane than needed for maximal response
Maximal biological responses is achieved
when only a small percentage of receptors are
occupied
Excess receptor number increases sensitivity of
the cell to low levels of hormone
Maximal stimulation of steroidogenesis by
Leydig cells occurs when only 1% of LH
receptors are occupied
Full steroid-induced transcriptional response
may only require 10% receptors
Plasma Membrane Receptors

More than one hormone can activate

the same intracellular signal
transduction
Example: Several hormones can activate
cAMP in the same cell
 Number of Receptors
Hormones regulate their own or other
hormone receptors.
Prolactin induces appearance of prolactin
receptors (up regulation)
Prolactin induces appearance of estrogen
receptors (results in synergy)
Chronic exposure of cells to insulin results
in decreased binding (down regulation) of
the insulin receptor.
 Receptors that Activate
G Proteins
Rall & Sutherland studied epinephrine (epi)
induced secretion of glucose from liver cells
Found in cAMP after epi treatment
Identified adenylyl (adenylate) cyclase
Orly & Schramm demonstrated that epi receptor
and AC were separate molecules
Fused adrenal tumor cells (active AC) with turkey RBC
(functional receptor)
 Intracellular Second Messengers*
Messenger Source Effect
cAMP Adenylyl cyclase Activates protein kinases
Activates protein kinases,
cGMP Guanylyl cyclase regulates ion channels,
regulates phosphodiesterases
Activates protein kinases,
Ion channels in ER and
Ca2+ activates Ca2+-modulated
plasma membrane
proteins
IP3 PLC action on PI Activates Ca2+ channels
DAG PLC action on PI Activates protein kinase C

Membrane component and Activates Ca2+ channels,

Phosphatidic acid
product of PLD inhibits adenylyl cyclase

PLC action on
Ceramide Activates protein kinases
sphingomyelin
Activates guanylyl cyclase,
Nitric oxide (NO) NO synthase
relaxes smooth muscle

Cyclic ADP-ribose cADP-ribose synthase Activates Ca2+ channels

*IP3 is inositol-1,4,5-trisphosphate; PLC is phospholipase C; PLD is phospholipase D; PI

is phosphatidylinositol; DAG is diacylglycerol.
Down regulation and Up regulation
Downregulation is the process by which a cell
decreases the quantity of a cellular component, such as
RNA or protein, in response to an external variable. An
increase of a cellular component is called upregulation.
An example of downregulation is the cellular decrease in
the number of receptors to a molecule, such as a hormone
or neurotransmitter, which reduces the cell's sensitivity to
the molecule. This phenomenon is an example of a locally
acting negative feedback mechanism.
An example of upregulation is the increased number of
cytochrome P450 enzymes in liver cells when xenobiotic
molecules, such as dioxin, are detected, which results in
degradation of the molecules.
Plasma Membrane Receptors

Receptors bind water soluble hormones and

transduce the signal
Some membrane receptors are enzymes
Some membrane receptors are coupled to G
(GTP-binding) proteins
Receptor Structure: transmembrane protein
Receptors that Activate G Proteins

Rodbell & Gilman et al. isolated and

showed the presence of a "Guanine
nucleotide binding protein" (G protein)
that mediated the effect of epi on AC
G - Protein
Synthesis and Breakdown of cAMP
Adenylyl Cyclase
Role of G Proteins
Role of G Proteins
(a) Adenylyl cyclase activity is modulated by the interplay of stimulatory
(Gs) and inhibitory (Gi) G proteins. Binding of hormones to b1- and b2-
adrenergic receptors activates adenylyl cyclase via Gs, whereas hormone
binding to a2 receptors leads to the inhibition of adenylyl cyclase.
Inhibition may occur by direct inhibition of cyclase activity by Gia or by
binding of Gibg to Gsa(GTP). (b) Two views of the complex of the VC1-
IIC2 catalytic domain of adenylyl cyclase and Gsa (c) Details of the Gsa
complex in the same orientation as the structures above.
Lipid-Soluble Hormones
What Turns the cAMP System Off?

Ga protein has inherent GTPase activity

Phosphodiesterase enzyme breaks down
cAMP AMP
Phosphatase enzymes remove PO4 groups
from proteins
Hormone/Receptor complex dissociates (or
becomes down-regulated )
Activation of Protein Kinase A

cAMP activates Protein Kinase A (PKA)

PKA phosphorylates various proteins in the
cell (ATP is PO4 donor)
PO4 put on OH groups of threonine & serine
of proteins (changes their shape)
Phosphorylation can either activate or
inactivate proteins (bc of change in shape)
Metabolic Action of Growth Hormone
Cellular Mechanism of
Hormone Action
35
Phosphatidylinositol/Phospholipase C System
 Signal Transduction Leads to
Cascade of Activity

Proteins Regulated by Phosphorylation:

Kinases: transfers PO4 onto proteins

Enzymes: regulate metabolism

Transcription factors: regulate gene activity

Adenylate cyclase-linked G-protein coupled receptors
The Proteins Phosphorylated by PKA
Depends on Cell Type

Different cell types contain different proteins

(enzymes)
Therefore, PKA activates different pathways
in different cells
Example:
PKA stimulates glycogen bkdn in liver
PKA stimulates lipid bkdn in adipose tissue
 Regulation of Blood Glucose
Levels
The
hyperglycemic
effects of
glucagon and
the
hypoglycemic
effects of insulin

Figure 16.18
Different signal molecules can
initiate the same response

Example: Epinephrine and glucagon

both initiate glycogen breakdown
 Calcium-Induced Calcium Release

IP3-mediated signal transduction pathways. Increased [Ca2+] activates protein kinases,

which phosphorylate target proteins. Ca2+/CaM represents calci-calmodulin (Ca2+
complexed with the regulatory protein calmodulin).
 Calmodulin (CaM)
Calmodulin (CaM) (an abbreviation
for CALcium MODULated proteIN) is a
calcium-binding protein expressed in all
eukaryotic cells. It can bind to and
regulate a number of different protein
targets, thereby affecting many different
cellular functions
Calmodulin
Zinc finger