Hormone

Hormone is substances released from ductless or endocrine glands

directly to the blood to control metabolism and biological activities in
target cell or organs.
properties of hormones
Low molecular weight ,Small soluble organic molecules, Rate of
diffusion is very high and are readily oxidized but the effect does not
remains constant, It is effective in low concentration ,Travels in blood, It
has its target site different from where it is produce and is specific to a
particular target.
Hormone production and release are primarily controlled by negative
feedback. In negative feedback systems, a stimulus elicits the release of a
substance; once the substance reaches a certain level, it sends a signal that
stops further release of the substance. In this way, the concentration of
hormones in blood is maintained within a narrow range. For example, the
amount of glucose in the blood controls the secretion of insulin and
glucagon via negative feedback
There are three mechanisms by which endocrine glands are stimulated to
synthesize and release hormones: humoral stimuli, hormonal stimuli, and
neural stimuli.
Humoral Stimuli
The term “humoral” is derived from the term “humor,” which refers to
bodily fluids such as blood. A humoral stimuli refers to the control of
hormone release in response to changes in extracellular fluids such as the
ion concentration in the blood. For example, a rise in blood glucose levels
triggers the pancreatic release of insulin. Insulin causes blood glucose
levels to drop, which signals the pancreas to stop producing insulin in a
negative feedback loop.
Hormonal Stimuli
Hormonal stimuli refers to the release of a hormone in response to another
hormone. A number of endocrine glands release hormones when
stimulated by hormones released by other endocrine glands. For example,
the hypothalamus produces hormones that stimulate the anterior portion of
the pituitary gland. The anterior pituitary in turn releases hormones that
regulate hormone production by other endocrine glands. For example the
anterior pituitary releases the thyroid-stimulating hormone, which then
stimulates the thyroid gland to produce T 3 and T4 hormones. As blood

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concentrations of T3 and T4 rise, they inhibit both the pituitary and the
hypothalamus in a negative feedback loop.
Neural Stimuli
In some cases, the nervous system directly stimulates endocrine glands to
release hormones, which is referred to as neural stimuli. Recall that in a
short-term stress response, the hormones epinephrine and norepinephrine
are important for providing the bursts of energy required for the body to
respond. Here, neuronal signaling from the sympathetic nervous system
directly stimulates the adrenal medulla to release the hormones
epinephrine and norepinephrine in response to stress.

Classification of hormones
Hormones are classified
A. On the basis of chemical nature:
1. Amino acid derivatives hormones: are derived from the amino
acid tyrosine like epinephrine, nor epinephrine
2. Peptide hormones (water soluble hormone): Peptide hormones
are hydrophylic and lipophobic (fat hating) – meaning they cannot
freely cross the plasma membrane They bind to receptors on the
surface of the cell, which are typically coupled to internally
anchored proteins (e.g. G proteins) The receptor complex activates a
series of intracellular molecules called second messengers, which
initiate cell activity This process is called signal transduction.
3. Lipid derivatives or steroid hormones: they are bound to
cytoplasmatic or nuclear receptors, in nucleus, the hormone-
receptor complex binds to HRE (hormone response element) in
regulation sequence of DNA. this leads to induction of mRNA
synthesis and transcription of gene

B. On the basis of mechanism of hormone action or the location of their

receptors :
I. Hormones with cell surface receptors: These hormones binds
to cell surface receptors and stimulates the release of certain
molecules (secondary messengers) to perform biochemical
functions.
On the basis of secondary messengers group I hormones are of 5 types

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I.A. Hormones bind with cell surface receptors with cAMP as the second
messenger such as ACTH, ADH, FSH HCG, LH, TSH , Calcitonin and
Glucagon.

I. B. Hormones having cell surface receptors; with cGMP as second

messenger such as ANF (atrial natriuretic factor), NO (nitric oxide).

I. C. Hormones having cell surface receptors; second messenger is

calcium or phosphatidyl inositol (PIP2) such as TRH, GnRH
catecholamines, Acetylcholine and Oxytocin.

I .D Hormones having cell surface receptors and mediated through

tyrosine kinase such as Insulin and Somatomedin.

I. E Hormones having cell surface receptors, but intracellular messenger is

a kinase and phosphatase cascade such as Erythropoietin, GH, PRL,
Adiponectin, Leptin and Resistin.

II. Hormones with intracellular receptors: These hormones are

lipophilic in nature. They are mostly derivatives of cholesterol.
Such as Mineralocorticoids, Estrogens, Androgens, Calcitriol and
Thyroxin

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Plasma carrier proteins exist for all classes of endocrine hormones. Carrier
proteins for peptide hormones prevent hormone destruction by plasma
proteases. Carriers for steroid hormones allow these hydrophobic
hormones to be present in the plasma. Carriers for small, hydrophilic
amino acid-derived hormones prevent their filtration through the renal
glomerulus.
Signal Transduction of Hormones with cell surface receptors through
G-Protein
Binding of different types of signal molecules(like hormone) to G-protein
coupled receptors (GPCRs) is a general mechanism of signal transduction.
Different types of G-proteins are present in the cells that are coupled with
different receptors and activating different effector proteins.
The inactive G-protein is a trimer with alpha, beta and gamma subunits.
When any ligand (like hormone-first messengers) binds, the GPCRs
activate heterotrimeric GTP binding regulatory proteins so named (G-
proteins). When activated, GTP binds to it lead to dissociation of the beta-
gamma subunits from the alpha subunit. The G-protein alpha subunit in
turn will interact with effector proteins which may be enzymes or ion
channel proteins (second messengers), which result then in the desired
effect.

Hormone binding activates G-protein

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Protein and Polypeptide Hormones Synthesis and Release
these hormones may have from 3 to 200 or more amino acid residues.
They include the pancreatic hormones insulin, glucagon, and somato
statin, the parathyroid hormone, calcitonin, and all the hormones of the
hypothalamus and pituitary.
protein hormones are synthesized in cells from amino acids according to
mRNA transcripts, which are synthesized from DNA templates inside the
cell nucleus. Preprohormones, peptide hormone precursors, are then
processed in several stages, typically in the endoplasmic reticulum (ER),
including removal of the N-terminal signal sequence and sometimes
glycosylation, resulting in prohormones. The prohormones are then
packaged into membrane-bound secretory vesicles, which can be secreted
from the cell by exocytosis in response to specific stimuli. These
prohormones often contain superfluous amino acid residues that were
needed to direct folding of the hormone molecule into its active
configuration but have no function once the hormone folds. Specific
endopeptidases in the cell cleave the prohormone just before it is released
into the bloodstream, generating the mature hormone form of the
molecule. Mature peptide hormones then travel through the blood to all of
the cells of the body, where they interact with specific receptor on the
surfaces of their target cells. When a peptide hormone binds to a receptor
on the surface of the cell, a second messenger appears in the cytoplasm,
which triggers signal transduction leading to the cellular responses.

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 Protein and Polypeptide Hormones Synthesis and Release

Cyclic AMP
Adenyl cyclase or adenylate cyclase converts ATP to CAMP (3’,5’-cyclic
AMP), and phosphodiesterase hydrolyzes cAMP to 5’ AMP. Cyclic AMP
is a second messenger produced in the cell in response to activation of
adenylate cyclase by active G-protein. During hormonal stimulation,
cyclic AMP level in the cell increases several times. The cAMP, in turn,
activates the enzyme, PKA (Cyclic AMP dependent protein kinase).
Cyclic AMP binds to the regulatory subunits of PKA so that the catalytic
subunits having kinase activity can phosphorylate proteins. This PKA is a
tetrameric molecule having two regulatory (R) and two catalytic (C)
subunits (R2 C2). This complex has no activity but when cAMP binds to
the regulatory subunit lead to dissociation of the tetramer into regulatory
and catalytic subunits, the catalytic subunit is now free to act. The
catalytic subunit then transfers a phosphate group from ATP to different
enzyme proteins. Phosphorylation usually takes place on the OH groups of

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serine, threonine or tyrosine residues of the substrates. Hence, these
kinases are called

Example for cell surface receptor hormone signal transduction with

cAMP as second messenger
Hypoglycemia lead to release of glucagon hormone ,after that glucagon
bind to target cell surface receptors leading to activation of cAMP
mediated cascade which activate Glycogen Phosphorylase which in turn
liberate glucose from glycogen. The termination of the effect of the
hormonal action by phosphorylation is effected by the action of protein
Phosphatases. Glycogen phosphorylase becomes inactive in the
dephosphorylated state; when cyclic AMP level falls, the regulatory
subunit is dephosphorylated and protein phosphatase becomes active,
which in turn hydrolyzes phosphate group from the enzyme. Protein
kinases as well as protein phosphatases are involved in the action of
different hormones.

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cell surface receptor hormone signal transduction with
Phosphatidylinositol/calcium as second messenger
The intracellular calcium concentration is low ,whereas extracellular
calcium concentration is very high maintaining a 10,000 fold calcium
gradient across the membrane. Even small increase in cytosolic free
calcium can have maximal effect on calcium regulated cellular functions.
There are mainly 3 types of calcium transport systems.
a. Voltage gated calcium channels
b. Sodium/calcium antiport transporter
c. Calcium transporting ATPase
The binding of hormones like serotonin to cell surface receptor triggers the
activation of the enzyme phospholipase-C which hydrolyses the
phosphatidyl inositol to diacylglycerol. IP3 can release Ca++ from
intracellular stores, such as from endoplasmic reticulum and from
sarcoplasmic reticulum . When cytosolic calcium increases, binding
regulatory proteins, activation of several calcium binding regulatory
proteins occurs. Calmodulin is expressed in various tissues and mediates
the regulatory actions of calcium ions. Calcium binding causes

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conformational change in calmodulin resulting in interaction with kinases
and phosphatases.

Diacylglycerol (DAG) Pathway DAG, the messenger formed by the

hydrolysis of PIP2 activates protein kinase C (PKC) which in turn would
phosphorylate other target proteins. DAG also increases the affinity of
protein kinase-C for calcium. The enzymes are thus activated, even at
physiological levels of calcium within the cell.
cell surface receptor hormone signal transduction with cGMP as second
messenger
Cyclic GMP (cGMP) is another important second messenger involved in
contractile function of smooth muscles, visual signal transduction and
maintenance of blood volume. Cyclic GMP degradation is catalyzed by
membrane bound phosphodiesterase (PDE). It is formed from GTP by the
action of guanyl cyclase. Several compounds have been found to increase
the concentration of cGMP by activating guanyl cyclase. These include
drugs like nitroprusside, nitroglycerine, sodium nitrite and atriopeptides.
All these compounds act as potent vasodilators, by inhibiting the
phosphodiesterase.
Cyclic GMP activates cGMP-dependent protein kinase G (PKG), which
phosphorylates important effector proteins that can regulate calcium
dependent contraction or motility through modulating calcium influx. •
NO (Nitric oxide) is the major activator of guanylate cyclase. NO in turn

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is produced by the action of NOS (Nitric oxide synthase) in tissues like
vascular endothelial cells. NO can easily diffuse through the membrane
and activate guanylate cyclase. Increased level of cyclic GMP in smooth
muscle triggers rapid and sustained relaxation of the smooth muscles.

Hormones with Intracellular Receptors

The hormones in this group include the steroid hormones and thyroid
hormones. They diffuse through the plasma membrane and bind to the
receptors in the cytoplasm.The hormone receptor (HR) complex is formed
in the cytoplasm. The complex is then translocate to the nucleus. In the
nucleus, the HR binds to the hormone response elements (HRE) or
steroid response elements (SRE).The SRE acts as an enhancer element and
when stimulated by the hormone, would increase the transcriptional
activity. The newly formed mRNA is translated to specific protein, which
brings about the metabolic effects. Steroid hormones influence gene
expression, so that the rate of transcription is increased. The stability of
mRNA is also increased. This would lead to induction of protein
synthesis. Steroid receptors have been found to enhance initiation of
transcription by formation of complexes at promoters.

hormonal signal transduction through intracellular receptors

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