2. Types of chemical messengers
• Endocrine hormones. These are the chemical messengers whose
function is the transmission of a molecular signal from a classic
endocrinal cell through the blood stream to a distant target cell.
• Neurocrine hormones. Neurohormones or peptides are released
from a neurosecretory neuron into the blood stream and then
carried to a distant target cells. Example of such neurocrine
substances are oxytocin and antidiuretic hormone.
• Paracrine hormones. These are chemical messengers which after
getting secreted by a cell in the ECF are carried over short distance
by diffusion through the interstitial spaces (extracellular fluid) to act
on the neighbouring different cell types
• Autocrine hormones. These refer to those chemical messengers
which regulate the activity of neighbouring similar type of cells
3. CLASSIFICATION OF HORMONES
• Depending upon the chemical nature
– Amines or amino acid derivatives; e.g.
• Catecholamines (epinephrine and norepinephrine) and
• Thyroxine (T4) and Triiodothyronine (T3).
– Proteins and polypeptides
• Posterior pituitary hormones (antidiuretic hormone and oxytocin),
• Insulin,
• Glucagon,
• Parathormone and
• Other anterior pituitary hormones.
– Steroid hormones. These include:
• Glucocorticoids,
• Mineralocorticoids,
• Sex steroids
4. Depending upon the mechanism of
action
• Group I hormones. These act by binding to
intracellular receptor and mediate their actions
via formation of a hormone–receptor complex.
These include steroid, retinoid and thyroid
hormones.
• Group II hormones. These involve second
messenger to mediate their effect. Depending
upon the chemical nature of the second
messengers, group II hormones are further
divided into four subgroups: A, B, C and D
5.
6. REGULATION OF HORMONE
SECRETION
• Feedback control
• Feedback control is of two types:
• Negative feedback control. Generally, the
influence of blood concentration of the hormone
concerned or its effect is to inhibit further
secretion of the hormone and is called negative
feedback control.
• Positive feedback control. It is less common, acts
to amplify the initial biological effects of the
hormone
7. Feedback control of hormonal
secretion
• Long-loop feedback - The peripheral gland hormone
(e.g. thyroid, adrenocortical, and gonads) can exert
long-loop negative feedback control on both the
hypothalamus and the anterior lobe of pituitary.
• Short-loop feedback - The pituitary tropic hormones
decrease the secretion of hypophysiotropic hormone
(e.g. GHRH, GHIH, TRH, GnRH, etc.) by short- loop
feedback.
• Ultra-short-loop feedback - The hypophysiotropic
hormones may inhibit their own synthesis and
secretion via negative feedback influence on
hypothalamus
8.
9. MECHANISM OF ACTION OF
HORMONES
• Action through change in membrane
permeability
• Certain hormones bind with the receptors
present in the cell membrane (external receptors)
and cause conformational change in the protein
of the receptors, this results into either opening
or closing of the ions channels (such as Na+
channels, K+ channels, and Ca2+ channels). The
movement of ions through Ca2+ channels causes
the subsequent effect, e.g. adrenaline,
noradrenaline act by this mechanism.
10. Action through effect on gene
expression by binding of hormones
with intracellular receptors
• Group I hormones act by their effect on the gene
expression include steroid hormones, retinoids
and thyroid hormones. These hormones are
lipophilic in nature and can easily pass across the
cell membrane. They act through intracellular
receptors located either in the cytosol or in the
nucleus. The sequence of events involved is:
– Transport. After secretion, the hormone is carried to
the target tissue on binding protein.
– Internalization. Being lipophilic, the hormone easily
diffuses through the plasma membrane.
11. • Receptor–hormone complex is formed by binding of
hormone to the specific receptor inside the cell.
• Conformational change occurs in the receptor proteins
leading to activation of receptors.
• The activated receptor–hormone complex then
diffuses into the nucleus and binds on the specific
region on the DNA known as hormone responsive
element (HRE), which initiates gene transcription.
• Binding of the receptor–hormone complex to DNA
alters the rate of transcription of messenger RNA
(mRNA).
• The mRNA diffuses in the cytoplasm, where it
promotes the translation process at the ribosomes. In
this way, new proteins are formed which result in
specific responses. Some of the new proteins
synthesized are enzymes
12.
13. ACTION THROUGH SECOND
MESSENGERS
• The peptides and biogenic amines act through second messenger
and are classified as group II hormones. Such hormones are also
called first messengers. The release of second messenger is
mediated by GTP binding proteins also called G-proteins.
• Coupling by G-proteins
• Events involved in coupling by G-protein which lead onto changes in
the cellular concentration of the second messengers are:
• Group II hormones are water soluble and bind to the plasma
membrane of the target cell via cell surface receptors.
• The hormone bearing receptor then interacts with a G-protein and
activates it by binding GTP. There are two classes of G-proteins:
stimulatory G-protein (Gs) and inhibitory G-protein (Gi).
• In its activated (“on”) state, the G-protein interacts with one or
more of the effector protein (most of which are enzymes or ion
channels such as adenylyl cyclase; Ca 2+ or K + channels or
phospholipase C, A2 or D) to activate or inhibit them. The changed
effector molecules, in turn, generate second messenger that
mediates the hormone’s intracellular action.
14. SECOND MESSENGER SYSTEMS
• The second messenger
systems that are activated
through coupling of
hormone–receptor
complexes by G-protein
include:
– Adenylyl cyclase–cAMP
system,
– Guanyl cyclase–cGMP
system,
– Membrane phospholipase–
phospholipid system and
– Calcium–calmodulin system.
15. Adenylyl cyclase–cAMP system
• The adenylyl cyclase–cAMP system was the first to be
described by Sutherland in 1961 that initiated the
concept of second messenger. The hormones which act
through this system constitute the group IIA hormones.
The steps involved in the hormone action via adenylyl
cyclase–cAMP system are summarized below :
• Binding of hormone (Step 1) to a specific receptor in
the cell membrane.
• Activation of G-protein (Step 2). After formation of
hormone–receptor complex, the GDP is released from
the G-protein and is replaced by GTP, i.e. G-protein is
activated.
16. • Activation of enzyme adenylyl cyclase (Step 3). The
hormone–receptor complex via activated G-protein
(stimulatory or inhibitory) either stimulates or inhibits
the enzyme adenylyl cyclase, which is also located in
the plasma membrane.
• Formation of cAMP (Step 4). Adenylyl cyclase when
activated, it catalyzes the formation of cAMP from
cytoplasmic ATP with Mg2+ as cofactor. A stimulatory G-
protein (Gs) therefore increases intracellular cAMP
levels, whereas an inhibitory G-protein (Gi) decreases
cAMP levels.
• Action of cAMP. The cAMP once formed stimulates a
cascade of enzyme activation. One molecule of cAMP
may stimulate many enzymes. Therefore, even a
slightest amount of hormone acting on the cell surface
can initiate a very powerful response. The cyclic AMP
so formed initiates response by different mechanisms
17.
18. Guanylate cyclase–cGMP
system
• Group II-B hormones which act via second
messenger
• cGMP include atrial natriuretic factor and nitric
oxide.
• Synthesis of cyclic GMP is analogous to the
formation of cAMP. Enzyme guanylate cyclase
produces cGMP from GTP.
• cGMP exerts its biochemical response through an
enzyme protein kinase G, which when activated
initiates a cascade of subsequent enzyme
activations.
19. Membrane phospholipase–phospholipid
system or IP3 mechanism
• Hormones which exert their response through this
system constitute the so-called group II-C hormones .
Steps involved in this system are :
– Hormone binds to a receptor in the plasma membrane.
– The hormone–receptor complex via a G-protein activates
the membrane enzyme phospholipase C.
– Activated phospholipase C then releases diacylglycerol and
inositol triphosphate (IP3) from the membrane
phospholipid.
– Inositol triphosphate (IP3) then mobilizes Ca2+from the
endoplasmic reticulum.
– Ca2+ ions and diacylglycerol together activate protein
kinase C.
– Activated protein kinase C phosphorylates proteins and
causes specific physiological action.
20.
21. Calcium–calmodulin system
• Hormones that act through this system as a second
messenger are also included in the so-called group-II C
hormone . Steps involved in this system are
• Hormone binds to a specific receptor in the plasma
membrane, then
• The hormone–receptor complex, via G-protein opens
the Ca2+ channels on the cell membrane and also
activates mobilization of Ca2+ bound to the
endoplasmic reticulum
• Ca2+ binds to a specific binding protein the calmodulin.
• The different calcium–calmodulin complexes activate
or deactivate various calcium-dependent enzymes
producing different physiological actions.
22.
23. Action of hormone via tyrosine kinase
activation
• Certain hormones act by activating tyrosine
kinase system and have been classified as
group-II D hormones. This mechanism of
signal generation from the plasma membrane
receptors does not require G-proteins. These
receptors have an extracellular hormone
binding portion, a single transmembrane
portion and an intracytoplasmic C-terminal
portion.
24. • The activation of tyrosine kinase occurs by two
mechanisms:
• Hormone receptors possessing intrinsic tyrosine
activity,
• e.g. those for insulin, involve following steps:
• Binding of hormone to the receptor changes its
conformation and exposes sites on its intracellular
portion that are capable of receptor
autophosphorylation at specific tyrosine sites.
• As a result, the receptor itself becomes a tyrosine
kinase that phosphorylates tyrosine residue on the
intracellular protein substrates.
• This latter activity sets into motion a cascade of events
leading to an enzyme activation and gene transcription
25. • Hormone receptors that do not possess intrinsic
tyrosine activity, e.g. those for growth hormone,
prolactin-releasing hormones, cytokines, etc. act as
follows :
• Hormone binding to extracellular portion of the
receptor changes its intracytoplasmic tail.
• The changes produced in the intracytoplasmic tail of
receptor exposes sites which attract and dock the
intracytoplasmic tyrosine kinases [such as janus
tyrosine kinases (JAK) and signal transducer and
activator of transcription (STAT) kinases] and then
activates them.
• The activated intracytoplasmic tyrosine kinases
phosphorylate cytoplasmic substrates, such as
transcription factor proteins and ultimately modulate
gene expression.
