Control of Endocrine Activity The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial. The concentration of hormone as seen by target cells is determined by three factors: 1.Rate of production: 2.Rate of delivery 3.Rate of degradation and elimination:
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Control of Endocrine Activity
The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial. The concentration of hormone as seen by target cells is determined by three factors:
1.Rate of production:
2.Rate of delivery
3.Rate of degradation and elimination:
Control of Endocrine Activity
[Hormone] as seen by target cells is determined by 3 factors:
Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits.
Rate of delivery: An example of this effect is blood flow to a target organ or group of target cells - high blood flow delivers more hormone than low blood flow.
Rate of degradation and elimination: Hormones have characteristic rates of decay, and are metabolized and excreted from the body via several routes. Shutting off secretion of a hormone that has a very short halflife causes circulating hormone concentration to plummet, but if a hormone's biological halflife is long, effective concentrations persist for some time after secretion ceases.
Hormone Synthesis
Diversity of hormones structuresLots of interesting pathways of biosynthesis
Simplest of hormones-amino acidsGlycine and glutamate -act as NTs in brain
F and Y-are precursors of dopamine, NE and EpiWhich also function as NTs
Hormone Synthesis
Y also substrate for generation of thyroid hormones
W is precursor for serotonin, a CNS NTand melatonin, a pineal hormone
Hormone Synthesis
Steroid Hormones
Made within the SERSteroid secreting cells easily recognized
Complex multiple enzyme system for synthesis secretion
Hormone Synthesis
Thyroid HormonesMade on protienaceous substrates outside the cell
ThyroglobulinThen taken up via endocytosis into the thyroid
gland-released from carrier protein prior to secretion from thyroid.
UNIQUE PROCESS
Hormone Synthesis
ProhormonesResult from cleavage events after translation
Even have preprohormones
ExamplesRenin (enzyme from Kidney)
Acts on angiotensinogen (substrate from liver)Results in ANGIOTENSIN I which is converted
by another enzyme to Antgiotensin II
Hormone Synthesis
Prohormones
Angiotensin II and bradykins are examples of hormones that are released from liver cells as larger prohormones
Hormone Synthesis
NTsMade in axon end of neurons
Neuropeptides like oxytocin and vasopressin also made in neurons
Hormone Synthesis
Summary
Variety of processes and intracellular locations involved
SER, RER, Cholesterol from inside and outside the cell,
Secretory pathway involved in hormone modifications, particulary
glycosylation
Control of Hormone Secretion
Most hormones are made within cellsare packaged in secretory vesicles until
released
-Except ….
Control of Hormone Secretion
Internal and external effectorsExtrinsic-light, sounds, smell, temp,
Etc.
Stimulation of hormone secreting cells results in vesicle fusion with the PM and exocytosis of secretory granules
Control of Hormone Secretion
Control of Hormone Secretion
Hormones often stimulate secretion of hormones from other endocrine glands
Pit hormones TSH, FSH, LH and ACTH simulate target tissue cells of
thyroid, adrenal, gonads to secrete their own hormones
Hormones control other hormonesCascade effect
Control of Hormone Secretion
Neuroendocrine transduction
stimulation of hormone secretion by nerves
Control of Hormone Secretion
Hormone interaction with some membrane receptors results in
membrane depolarization-stimulates movement of Ca++into cells which
results in sec. vesicle exocytosis
Some chemical messenger inhibit secretion by resulting ……
Hormone Delivery
Several routes of delivery1.Endocrine
2. neurocrine- neuron contact target cell and releases hormone
3. neuroendocrine-neuron to blood4. Paracrine
5.lumonal-released into lumen of the gut
6. AutocrineSome delivered by all these routes
Hormone Circulation and metabolism
Peptide hormones have short half lives
Broken down by …
Most steroid hormones bound to plasma proteins. Steroid hormones
much more stable
Feedback Control of Hormone Production
Feedback circuits are at the root of most control
mechanisms in physiology, and are particularly prominent
in the endocrine system.
Instances of positive feedback certainly occur, but negative
feedback is much more common.
Feedback Control of Hormone Production
Negative feedback is seen when the output of a pathway inhibits
inputs to the pathway.
The heating system in your home is a simple negative feedback circuit.
Feedback loops are used extensively to regulate secretion of hormones
An important negative feedback loop is seen in control of thyroid hormone secretion. The
thyroid hormones thyroxine and triiodothyronine ("T4 and T3") are synthesized
and secreted by thyroid glands and affect metabolism throughout the body.
The basic mechanisms for control in this system (illustrated on next slide) are:
1.Neurons in the hypothalamus secrete thyroid releasing hormone (TRH), which stimulates cells in the anterior pituitary to secrete thyroid-stimulating hormone (TSH).
2. TSH binds to receptors on epithelial cells in the thyroid gland, stimulating synthesis and secretion of thyroid hormones, which affect probably all cells in the body.
3.When blood concentrations of thyroid hormones increase above a certain threshold, TRH-secreting neurons in the hypothalamus are inhibited and stop secreting TRH. This is an example of "negative feedback".
Inhibition of TRH secretion leads to shut-off of TSH secretion, which leads to shut-off of thyroid hormone secretion. As thyroid hormone levels decay below the threshold, negative feedback is relieved, TRH secretion starts again, leading to TSH secretion ...
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Target cell response
TRH receptors only found in anterior pituitary
TSH receptors only found in thyroid gland
TH receptors found on every cell
Cascade effect
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Another type of feedback is seen in endocrine systems that regulate concentrations of blood components such as glucose.
Drink a glass of milk or eat a candy bar and the following (simplified) series of events will occur:
Glucose from the ingested lactose or sucrose is absorbed in the intestine and the level of glucose in blood rises.
Elevation of blood glucose concentration stimulates endocrine cells in the pancreas to release insulin.
Insulin has the major effect of facilitating entry of glucose into many cells of the body - as a result, blood glucose levels fall.
When the level of blood glucose falls sufficiently, the stimulus for insulin release disappears and insulin is no longer secreted.
Numerous other examples of specific endocrine feedback circuits will be presented in the sections on specific hormones or
endocrine organs.
Hormone Profiles: Concentrations Over Time
One important consequence of the feedback controls that govern hormone concentrations and the fact that hormones have a limited lifespan or half-life is that most hormones are secreted in "pulses". The following graph depicts concentrations of LH in the blood of a female dog over a period of 8 hours, with samples collected
every 15 minutes:
The pulsatile nature of LH secretion in this animal is evident.
LH is secreted from the anterior pituitary and critically involved in reproductive function; the frequency and amplitude of pulses are quite different at different stages of the reproductive cycle.
With reference to clinical endocrinology, examination of the graph should also demonstrate the caution necessary in interpreting endocrine data based on isolated samples.
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A pulsatile pattern of secretion is seen for virtually all hormones, with
variations in pulse characteristics that reflect specific physiologic states. In addition to the short-term pulses discussed here, longer-term temporal
oscillations or endocrine rhythms are also commonly observed and undoubtedly
important in both normal and pathologic states.
Mechanisms of Hormone Action
Immediately after discovery of a new hormone, a majority of effort is devoted to delineating its sites of synthesis and target cells, and in
characterizing the myriad of physiologic responses it invokes. An equally important area of study is to determine precisely how the hormone acts to change the physiologic
state of its target cells - its mechanism of action.
Mechanisms of Hormone Action
Understanding mechanism of action is itself a broad task, encompassing
structure and function of the receptor, how the bound receptor transduces a
signal inside the cell and the end effectors of that signal. This information is not only
of great interest to basic science, but critical to understanding and treating
diseases of the endocrine system, and in using hormones as drugs.
Physiological roles of Hormones
Hormones control of activity of all cells in the body
Affect cellular synthesis and secretion of other hormones
After metabolic processes (catabolic and anabolic). Turnover of sugar,
proteins and fats
Affect Contraction, relaxation and metabolism of Muscle
Physiological roles of Hormones
Reproduction
Cell growth and proliferation
Excretion and reabsoroption of ions
Affect action of other hormones
Role in animal behavior
Physiological roles of Hormones
Some hormones only exist a few times in the life of an individual hCG
Sometimes still have hormone but not sensitive to it any longer
Sometimes no longer produce hormone-thyroid hormone, estrogen
General mechanisms of Hormone
action
ReceptorsSecond messengers
Phosphorylation involves STYKinases and phosphatases
Reminder about
General mechanisms of Hormone action
Steroid hormones have intracellular receptors.
So do Thyroid hormones
Endocrine pathophysiology
Failure of a gland to secrete enough hormone can lead to fatal consequences
No insulin-hyperglycemia-coma and death if untreated
General mechanisms of hormone action
Hormones regulate specific target tissuesNOT ALL CELLS IN the body
Determined by??Receptors-proteins bind hormones
Contribute to specificity of action
Can be PM or cytosolic or nuclear
Hormone response effected by Receptor Levels and hormone levels
Oxy and vasopressin AVP have similar structure and both hormones stimulate uterine smooth muscle contraction and
activate renal cAMPUterine receptors more sensitive to OXY
Renal receptor more sensitive to AVPNormal hormone conc. Each hormone only
activate appropriate cell type
Hormone response effected by Receptor Levels and hormone levels
When one hormone binds to the receptor of another hormone, this is called
CROSS TALK
Happens with lots of hormones.If hormone levels are high, will not only act
on its own receptor, but similar hormone receptors
Some hormones stimulate a number of tissues.
Insulin stimulates glucose uptake into skeletal muscle and Fat cells
But also talks to liver to shut down output of glucose from liver
High Insulin receptor levels on fat, muscle and liver, but low levels in
other tissues.
Insulin receptors at high levels in skeletal muscle
Fat cellsLIVER
Cells where INSULIN MODULATES glucose metabolism
Insulin receptors at low levels in all other tissues where this hormone
only has a modest effect on GROWTH
DOES NOT MODULATE GLUCOSE METABOLISM IN
THESE OTHER TISSUES
RECEPTORS FOR A PARTICULAR HORMONE ARE ONLY EXPRESSED IN CELLS
WHERE THE HORMONE ACTS.MORE ACTION-MORE
RECEPTORS
UNDERSTAND INSULIN EXAMPLE (IT IS AN
EASY ONE)
Hormone response effected by Receptor Levels and hormone levels
Have high levels of receptor in tissue that are primary responders
Hormones act via own receptors at normal concentrations
High hormone concentration can act on similar receptors
NE and EpiOxy and vaso
IGF-1 and insulin
In most cases, a maximum biological response to a
hormone is achieved when only a small % of the
receptors are occupied.
WHY?
There are 4 classes of membrane bound receptors
1. Those that are enzymes (have tyrosine kinase activity)
2. Ion channels3. Receptors coupled to G proteins
4. Receptor that don’t have enzymatic activity (utilize the JAK STAT
pathway)
Peptide hormones act via PM receptors
There are 4 classes of membrane bound receptors
1. Those that are enzymes (have tyrosine kinase activity)
There are 4 classes of membrane bound receptors
1. Those that are enzymes (have tyrosine kinase activity)
This means the receptor itself has enzymatic activity when the hormone
is bound.Usually KINASE activity
KINASE activity
X-OH X-OP
Phosphatase activity
Amino acid substratesS T Y
There are 4 classes of membrane bound receptors
1. Those that are enzymesInsulin receptorEGF receptorNGF receptor
Usually induce cascade effect
2. Ion channelsLigand binding changes the conformation of
the receptor so that specific ions flow through it; the resultant ion movements alter the electric potential across the cell
membrane. The acetylcholine receptor at the nerve-
muscle junction
There are 4 classes of membrane bound receptors
3. Receptors coupled to G proteins (7TMDS)
Odorant ReceptorsAdrenergic receptors
(epi and NE)
7 hydrophobic membrane spanning domainsInternal G protein interacting region
N terminal glycosylationC-term phosphorylation sites
Mediate signals for proteins, peptides, NTOdorants and photons
hydrophobic membrane spanning domains22 -28 hydrophobic AA
Many of the receptors for peptide hormones and NTs are linked to G
proteins
Most neuropeptide receptors
There are 4 classes of membrane bound receptors
4. Receptor that don’t have enzymatic activity (utilize the JAK STAT
pathway)Examples
GH receptor, PRL receptorCardiotrophin 1 (CT1), CNTF receptor
Leptin receptor
The JAK/STAT Signaling Pathway
JAK STAT pathway Ligand binds receptor
Receptor DimerizesReceptor associate with JAK kinase
JAK phosphorylates receptorSTAT associates with phosphorylated
receptorJAK phosphorylated STAT
STAT forms dimer and translocates to the nucleus to regulate transcription
JAK STAT pathway
Used by Growth HormoneAnd prolactin
And EPOInterferons
There are 4 classes of membrane bound receptors
1. Those that are enzymes (have tyrosine kinase activity)
2. Ion channels3. Receptors coupled to G proteins
4. Receptor that don’t have enzymatic activity (utilize the JAK STAT
pathway)
Second Messengers of Hormone Action
Cyclic NucleotidesGenerated by Nucleotide cyclyzing
enzymes-located on inner surface of PM
ATP cAMPAdenylate cyclase
GTP cGMPguanylate cyclase
cAMP and cGMP Combine with cyclic dependent protein
kinases cAMP associates and activates
cyclic dependent protein kinase A (PKA)2 Regulatory and 2 Catalytic subunitscAMP binds R subunits which frees C
which has enzymatic activity
Genomic actions of cAMP Many second messengers, result in
immediate responseOthers have actions which are blocked
by actino. D or Cyclohex.For example, PKA activates CREB
cAMP response element binding proteinCREB binds gene promoters are CRE
elements (camp responsive elements) to modulate transcription
Enzyme phos. Leads to a cascade effectResults in amplification
So little hormone or second messenger have a large effect
X-OH X-OP
y-OH y-OP
z-OH z-OP
cAMP and cGMP rapidly metabolized
Action of kinasesReversed by phosphatases
When initiate a response, also initiate a means to inhibit response
cAMP and cGMP getInactivated by phosphodiesterases (PDE)
To 5’AMP or 5’ GMP cyclase
Activity of PDEs inhibited by methylxanthines
Caffeine, theophylline, and theobromineIncreased cAMP/signaling
Many hormones use adenylate cyclase to cause a physiological response.
Some activate this enzymeOthers can inhibit
Receptor G-protein interactions mediate different signal transduction pathways
PLCAdenylate cyclase
PLA2Ion Channel*
*G proteins don’t always induce Second Messenger
Some Second Messengers
Multiple Membrane Messengers
PI (phosphoinosotides) are phospholipids in PM of all eukaryotes
Breakdown to form second messengers• AA• IP3
• DAG
Protein Kinase C (PKC)Multifunctional enzyme
Many typesCa++ dependent and independent
Inactive until associates with PM then activated by DAG
Active enzyme is membrane boundPKC-many roles including growth and
proliferation. Activated by most peptide mitogenic hormones
Eicosanoids and Hormone Action
Eicosanoids are produced by cells in response to some hormones
Intracellular second messengers1982 Nobel Prize
They are rapidly degraded, so they are not transported to distal sites within the body.
Eicosanoids and Hormone Action
Common EicosanoidPGE2PGF2a
Prostacylin (PGI2)
PGI2 and PGE2 can activate adenylate cyclase
Eicosanoids are produced exclusively
within the PMPrimarily derived from AA that is release from phospholipids via action
of PLA2
AA can also produce leukotrienesAA----5HPETE by
5’lipoxgenase
Prostacyclin (PGI2)
Produced by blood vessel wallMost potent natural inhibitor of blood
platelet aggregationActivates AC which increase cAMP Which inhibits platelet aggregations
ThromboxaneA2 specific product of the platelets
2 types of prostaglandins thromboxane (vasoconstrictor) and PGI2
(vasodilator) Opposite effects
A vasoconstrictor is any substance that acts to constrict blood vessels
Vasoconstrictors are also used clinically to increase blood pressure or to reduce local blood flow.
LeukotrienesMade by leukocytes
Important in vascular contraction and permeability
Lots of diseases associated with increased levels
AsthmaChronic bronchitis, CF, septic shock
Psoriasis, Inflamm Bowel Dis
Many prostaglandins act as local mediators -paracrine and autocrine signaling
Destroyed near the site of their synthesis. Modulate the responses of other hormones and can have
profound effects on many cellular processes.
Certain prostaglandins cause blood platelets to aggregate and adhere to the walls of blood vessels. Because
platelets play a key role in clotting blood and plugging leaks in blood vessels, these prostaglandins can affect
the course of vascular disease and wound healing; aspirin inhibits their synthesis by acetylating
prostaglandin H2 synthase.
Not all hormones work via cell surface receptors
Steroid and Thyroid Hormone receptors
Receptors are present in cytosol and/or nucleusEstrogen and estrogen receptor (ER)
Testosterone and androgen receptor (AR)Thyroid hormones and Thyroid hormone
receptors (TR)Cortisol and Glucocorticoid receptor (GR)
Hormones enter cell by diffusion (hydrophobic)
Usually bind receptor in cytosol (displace a binding protein)
Translocates to the nucleusBinds promoter at specific elements
Regulates gene expression
Hormone/receptor complex translocates to the nucleus and binds promoters at
Can be used to determine if an action of a hormone is genomic
Specific Example
To determine if effect of a hormone is dependent on new proteins synthesis, treat target cells with CH then look at
hormone action.
If action is blocked, know the effect is genomic
Pharmacological experiments
Colchicine and Cytochalasin can be used to tell if signaling or secretion is
dependent on cytoskeleton
Tissue Extracts and purification
Type I diabetics need daily injections of insulin
Used to come from pigs, cattle, horse.Slaughterhouse blood
Contaminants from animalsSpecificity issues
Insulin now made recombinant
Sheep melatonin Bovine GH
Tissue Extracts and purificationDisadvantage of using hormones
purified from animals or Slaughterhouse blood
-Contaminants from animals-Specificity issues
-Cost, much cheaper to make recombinantly
Sheep melatonin Bovine GH
Recombinant DNA methods
Way in which we make insulin
Genetic engineering in various speciesFish, mice, rats.
Transgenic Animals
introduce gene in animal-Usually replace wild type with a mutant
-Or express gene from a different promoter.
Transgenic Mice over expressing TropomodulinHave enlarged right atrium and ventricle and are larger
Labeled for two different proteins which are normally present in myofibrils. The alternating bands of tropomodulin (green) and alpha-
actinin (red) show the dense packing of myofibril throughout the interior of the cell.
The normal alternating pattern of tropomodulin and alpha-actinin immunoreactivity has been disturbed. The yellow color indicates
colocalization of both red and green labels (an abnormal distribution). Transgenic mice with this level of tropomodulin overexpression suffer
from cardiomyopathy
transgenic mice that
overexpress TGFß1 in the CNS
animals developed severe hydrocephalus
transgenic colony serves as a model of congenital
hydrocephalus
GH receptor
knockout
GFP mice
overexpress neurotrophin-3 (NT-3) in skeletal muscle
When lifted by the tail, wildtype extend their hindlimbs and digits. In contrast, all transgenic NT-3 mice retract their hindlimbs to the body and clench their paws in a
"clasping phenotype"
Transgenic mice has different
coat color
Transgenic mice extremely useful in studying diseases