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Neuroendocrinology
Neuroendocrinology
Neuroendocrinology
Hypothalamus and Pituitary
• Hypothalamus-pituitary unit is the most
dominant portion of the endocrine system
• Regulates the function of the
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Thyroid
Adrenal
Reproductive glands
Controls somatic growth
Lactation
Water metabolism
The pituitary releases hormones that
induce or inhibit the release of other
hormones
The Hypothalamic-Pituitary unit
Posterior pituitary
(Neurohypophysis)
• An outgrowth of the
hypothalamus
composed of neural
tissue.
• Hypothalamic
neurons pass
through the neural
stalk and end in the
posterior pituitary.
• 2 Hormones are
released
(ADH)
Anterior pituitary
(Adenohypophysis)
• AP is connected
to the
hypothalamus by
the superior
hypophyseal
artery.
Median eminence
Releasing
Hormones
• The AP produces
six hormones:
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Prolactin (PRL)
Growth hormone (GH)
Thyroid stimulating
hormone (TSH)
Adrenocorticotropic
hormone (ACTH)
Follicle-stimulating
hormone (FSH)
Luteinizing hormone (LH)
AP Hormone release
Hypothalamic releasing hormones
Hypothalamic releasing hormone
Effect on anterior pituitary
Corticotropin releasing hormone
(CRH)
Thyrotropin releasing hormone
(TRH)
Growth hormone releasing
hormone (GHRH)
Somatostatin
Stimulates ACTH secretion
Gonadotropin releasing hormone
(GnRH)
Prolactin releasing hormone (PRH)
Prolactin inhibiting hormone
(dopamine)
Stimulates TSH and Prolactin
secretion
Stimulates GH secretion
Inhibits GH (and other hormone)
secretion
Stimulates LH and FSH
secretion
Stimulates PRL secretion
Inhibits PRL secretion
Characteristics of hypothalamic
releasing hormones
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Secretion in pulses
Act on specific membrane receptors
Transduce signals via second messengers
Stimulate release of stored pituitary hormones
Stimulate synthesis of pituitary hormones
Stimulates hyperplasia and hypertophy of target
cells
• Regulates expression of its own receptor
Hormones of the
Anterior pituitary
Hormones of the
Anterior pituitary
Hormones of the
Anterior pituitary
Hormones of the
Anterior pituitary
Hormones of the
Anterior pituitary
Regulation of endocrine axes
HPA axis
CRH
ACTH
Adrenals
Cortisol
Endocrine signalling
- Hormones are synthesised and secreted by cells in
endocrine glands
- They enter bloodstream, are distributed throughout
body and can act at distant target sites
• Each hormone acts only on certain cells
– Cells respond only when they have receptors for
the hormone in question
• Is slower than nervous system control
• Endocrine and nervous system to interact with one
another
Endocrine signalling
• All cells potentially exposed to all hormones via
circulation
• Only cells with specific receptor for specific
hormone can respond
• Because of dilution in blood stream, [hormone]blood
are very low (10-9 mol.l-1; nM)
• Receptors must bind hormones very effectively i.e.
they must have a high affinity for the specific
hormone
2 types of hormone receptors
Steroid hormone
Intracellular receptor
Non-steroid hormone (peptide)
Cell surface receptor
Receptors & Downstream Signalling
Receptors
• 4 main types of receptor:
– Ionotropic (Ion channel linked)
– Metabotropic (G protein-coupled)
– Kinase linked receptors
– Intracellular receptors
Transmembrane
Receptors
Ion channel receptors
• Ligand-gated ion channels
•
Protein pores in the plasma membrane that open
or close in response to a chemical signal.
G-Protein-coupled Receptors
cAMP as a 2nd
messenger
Gs
• Neurotransmitter
• Adrenaline acting
at -adrenoceptors
• Hormone
• ACTH acting at
ACTH receptors
cAMP as a 2nd
messenger
Gs
• Neurotransmitter
• Adrenaline acting
at -adrenoceptors
• Hormone
• ACTH acting at
ACTH receptors
• Inhibitory regulation
of adenylyl cyclase via
receptors linked to Gi
  cAMP levels
2nd messengers
- Small molecules that spread throughout the cell easily
- Participate in pathways initiated by G-protein-linked
receptors and tyrosine-kinase receptors.
Most widely used:
-Cyclic AMP
-IP3/Calcium ions (Ca2+)
Cyclic Adenosine Monophosphate (cAMP)
Signal Amplification
cAMP as a 2nd
messenger
• Neurotransmitter
• Adrenaline acting
at -adrenoceptors
 subunit can also activate
ion channels directly
• Hormone
• ACTH acting at
ACTH receptors
 subunit can also activate
ion channels directly
Specificity of cell signaling
Cells can react differently to certain signals,
because different kinds of cells have different
collections of proteins.
Cellular response to adrenaline in liver via
-adrenoceptor activation
Inositol trisphosphate signaling pathway
Another 2nd messanger pathway
PM
PI is a phospholipid found
in the plasma membrane
IP3 and DAG as
2nd messengers
(eg) Serotonin action
at 5-HT2 receptors
DAG activates
protein kinase C
Tyrosine-Kinase Receptors
• Receptors with enzymatic
(Kinase) activity
– Phosphorylate tyrosine residues
• Examples
– Insulin
– Nerve Growth Factor
– Cytokines such as IL-6, IL-10, IFN-
• Steps in receptor activation:
• Ligand binds causing the two
receptor polypeptides to dimerize
• Tyrosine kinase activation
• Phosphorylation of tyrosine
residues on the tail of the other
polypeptides
Protein phosphorylation cascades:
A central mechanism of signal transduction
• Protein kinase: an enzyme that transfers phosphate groups from
ATP to a protein
– Usually phosphorylate either serine, threonine or tyrosine residues
– Abundant relay molecules in signal transduction cascades
– Often phosphorylate each other
• The signal is transmitted by a series of phosphorylations, each
bringing with it a conformational change
• Protein kinases are very important
– Regulate a large number of the proteins in the cell
• Protein phosphates: enzymes that remove phosphate groups from
proteins
– The effects of protein kinases are rapidly reversed in the cell by protein
phosphates
– Balance between kinases and phosphatases is important
Signaling pathways into the nucleus
• Some signaling pathways regulate the synthesis of enzymes or
other proteins - not their activity.
• Transcription factors control which genes are turned on. It’s
activity may be regulated by a signaling pathway that extends
into the nucleus
Signal transduction can
result in activation of a
transcription factor
Signal transduction can
result in activation of a
transcription factor
Example
cAMP – PKA - CREB
Steroid hormone receptors: Mechanism of action
Glucocorticoid
(Cortisol)
Altered gene
expression
Nucleus
Cytoplasm
The stages of cell-cell communication
• Cell signaling can be spilt into four steps
• Release of signalling molecule:
– Neurotransmitter, hormone, growth factor released
• Reception:
– The target cell detects a signal coming from outside of the cell.
– Usually occurs when the signaling molecule binds to a receptor
– When the signal binds to the receptor protein, it’s changed in some
way. This initiates the process of transduction.
• Transduction:
– The signal is converted to a form that can bring about a specific
cellular response.
– Normally requires a sequence of changes in a series of different
molecules.
– Molecules in the pathway often called relay molecules.
• Response:
– Transduced signal triggers a specific cellular response
The stages of cell-cell communication using chemical
messengers
Mediator release
Receptors types and signalling mechaisms: overview