W9 - Neurohormones

Question 1

What are the different types of neurotransmission?

Answer 1

A: Point to point communication-Fast, restricted
B: Neurons of secretory hypothalamus-slow but widespread
C: Networks of interconnected neurons Autonomic Nervous System-fast, widespread influence
D: Diffuse modulatory systems-slower, widespread

Question 2

What are the 2 main control systems of the body and how do they compare?

Answer 2

ENDOCRINE SYSTEM
* Mediators travel within blood vessels
* Utilises chemical mediators (hormones)
* Slow communication
* Effects can be long-lasting

NERVOUS SYSTEM
* Signalling along nerve fibres
*Transmission of electrical impulses
* Fast communication
* Effects are generally short-acting

Neurohormones are produced by specialised nerve cells called neurosecretory cells and released into the blood. Because they are defined as hormones, they
are secreted into the blood and have their effect on cells some distance away, but the same compounds can also act as neurotransmitters or as autocrine
(self) or paracrine (local) messengers.

Question 3

What are the types of hormones?

Answer 3

• Protein & Peptide hormones
• vary considerably in size.
• can be synthesised as a large precursor and processed prior to secretion (e.g. GH, somatostatin, insulin)
• can be post-translationally modified (e.g. glycosylation)
  _can have multiple subunits synthesised independently and assembled
  (e.g. FSH, LH, TSH)

*Amino acid derivatives
⁃ Mostly tyrosine derived
⁃ Neurotransmitter that can also act as a hormone e.g. Epinephrine, Norepinephrine, Dopamine

*
Steroid hormones

- Steroid is a class of lipids derived from cholesterol.
-
- Include Cortisol, Aldosterone, Testosterone, Progesterone, estradiol

Question 4

What are neuropeptides?

Answer 4

Neuropeptides (neurohormones) are functionally important transmitters in the Hypothalamo-pituitary axis. The HPA has 2 components (anterior and posterior pituitary)

The pituitary lies on a bony structure called sella turcica. The hypothalamus and pituitary are linked via a stalk-like structure. There is a capillary network in both these structures. The hypothalamus is connected to the anterior pituitary via a portal system.

Hypothalamus is connected to the posterior pituitary via magnocellular neurones. The cell bodies are located on the specific nuclei of hypothalamus. Once these are activated, they release neurones directly in the capillary network of posterior pituitary. These are neurohormones. The neurohormones are derived directly from genes. These then activate specialised cells to release hormones like LH.

Question 5

What is the anatomy of hypothalamo-hypophyseal system?

Answer 5

The pituitary lies in a bony cavity (sella turcica or pituitary fossa) in the sphenoid bone. The pituitary is connected to the hypothalamus by a stalk.
The hypothalamic hormones are secreted into the portal vein system at the median eminence.
The delivery of these hormones is dependent on an intact pituitary stalk (infundibulum).
Any damage of the pituitary stalk will result in failure of gonadal, thyroid and adrenal function, as well as mis-regulation of growth.

A number of these peptides act both as hormones and as neurotransmitters; sometimes the endocrine and neural functions are linked in others they are not.

The neuroendocrine secretory cells are scattered in the hypothalamus but key nuclei are the medial pre-optic, the arcuate and the paraventricular nuclei.

The magnocellular neurones are located in the paraventricular nuclei and supraoptic nuclei. These project directly to the posterior pituitary gland to release oxytocin and vasopressin.

Vasopressin acts on the kidneys as an antidiuretic hormone and will also increase blood pressure.

Oxytocin is located in mammary glands - eg. helps with milk ejection. Also helps with uterine contractions during labour.

Question 6

What are the hypothalamic neurohormones that control the anterior pituitary?

Answer 6

• Corticotrophin Releasing Hormone (CRH):
  41 a.a. peptide that controls the release of adrenocorticotrophin (ACTH). This goes onto release cortisol.
• Thyrotrophin Releasing Hormone (TRH):
  3 a.a. peptide that controls the release of thyroid stimulating hormone (TSH) and prolactin (PRL).

*Gonadotrophin Releasing Hormone (GnRH):
10 a.a. peptide that controls the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH).

*Growth Hormone Releasing Hormone (GHRH):
44 a.a. peptide that controls the release of growth hormone (GH).

*Growth Hormone Release Inhibiting Hormone (Somatostatin):
14 a.a. peptide that inhibits release of GH, gastrin vasoactive intestinal polypeptide (VIP), glucagon, insulin, TSH and PRL.
Dopamine: a monoamine that inhibits the release of PRL

Question 7

What are some specialised cells responding to the hypothalamic hormones?

Answer 7

The anterior pituitary contains specialised cells responding to these hypothalamic hormones:
⁃ Gonadotroph cells that secrete LH and FSH in response to GnRH.
⁃ Somatotrophs that control GH secretion in response to GHRH.
⁃ Corticotrophs that control ACTH secretion in response to CRH.
⁃ Thyrotrophs that regulate TSH secretion in response to TRH.
⁃  Lactotrophs that control the secretion of prolactin in response to
TRH, somatostatin & dopamine.

Question 8

What are the adrenocorticotrophic hormone (ACTH)?

Answer 8

HP axis is activated through stress. Two thing happen when this occurs:
1) Major release of noradrenaline = increase arousal
2) Activation of HP axis

Stress = Hypothalamus = CRH = Pituitary = ACTH = Adrenal cortex = Cortisol
Cortisol then mobilises energy stores, which copes with stress. When cortisol increases, a negative feedback occurs where the cortisol binds on to the cortisol receptors in the pituitary and hypothalamus. These will then inhibit the release of CRH, so ACTH.

Aka adrenocorticophin.
ACTH is 39 a.a. peptide with a molecular weight of 4.5kDa. Belongs to a family of related peptide hormones derived from a large
precursor glycoprotein, pro-opiomelanocortin
(POMC).
Hypothalamic neurones release corticotrophin
releasing hormone (CRH) to stimulate pituitary
corticotrophs to release ACTH into the circulation.
ACTH stimulates the production of
glucocorticoid and sex hormones from the
zona fasciculata of adrenal cortex.
*Cortisol is a steroid hormone, more specifically a
glucocorticoid. Hydrocortisone is a name for cortisol
used as a medication.

Question 9

What do the Glucocorticoid secretion shows rhythms of peaks and troughs mean?

Answer 9

Cortisol levels are linked with the circadian rhythm. It is very high first thing in the morning and continues to decrease throughout the day. This is why it needs to be measured at the same time each day.

Following changes in brain activity, plasma cortisol levels are highest first thing in the morning and decline during the day (reflecting the pattern of ACTH secretion by the anterior pituitary). This circadian rhythm must be taken into account when considering cortisol replacement therapy as a clinical treatment. The pattern of cortisol secretion probably reflects the body’s response to low blood glucose after overnight fasting.

Question 10

What is a good example of endocrine control?

Answer 10

A good example of endocrine control is the regulation of TSH and thyroid secretion by negative feedback.

Thyrotrophic releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).
TSH acts on the thyroid to increase T4/T3 secretion. T3 is the most potent thyroid hormone and target tissues contain a deiodinase enzyme (DI) to convert T4 to T3.The pituitary also expresses deiodinase to convert T4to T3 to facilitate negative feedback.

High thyroxine = anxiety
Low thyroxine = depression

Question 11

What are the hypothalamic neurohormones that regulate posterior pituitary?

Answer 11

Vasopressin & Oxytocin
⁃ Synthesised in the supraoptic and paraventricular nuclei in the hypothalamus
⁃ Transported to the terminals of the nerve fibers located in the posterior pituitary
⁃ Structurally quite similar, yet have very different functions.

Question 12

What is Vasopressin?

Answer 12

Aka anti-diuretic hormone (ADH).
Release is stimulated by changes in the activity of the osmoreceptor complex in the hypothalamus.
Controls plasma osmolality by regulating water excretion & drinking behaviour.
Stimulates vascular smooth muscle contraction in the distal tubules of the kidney to reduce loss of water and raise blood pressure.

In response to low BP, kidney releases Renin.
Renin converts angiotensinogen to angiotensin I, which is converted to angiotensin II, which constricts blood vessels to increase blood pressure.
Angiotensin II also acts on the Subfornical organs, which stimulates magnocellular neurones to release ADH directly in the blood circulation. It would also induce thirst - drink water.

Question 13

What is Oxytocin?

Answer 13

Normally undetectable, but elevated during parturition, lactation and mating.
Released in response to peripheral stimuli of the cervical stretch receptors and suckling at the breast.
It may also be involved in responses to stroking, caressing, grooming.
Regulates contraction of smooth muscles (e.g. uterus during labour, myoepithelial cells lining the mammary duct, contraction of reproductive tract during sperm ejaculation).

Question 14

What is the two way interaction between the kidneys and hypothalamus?

Answer 14

• Kidneys
• Secrete renin
• Renin converts Angiotensinogen to Angiotensin I.
• Angiotensin I is converted in Angiotensin II
• Angiotensin II is detected by the subfornical organ
• Subfornical organ projects to vasopressin cells and neurons in the lateral hypothalamus
• Vasopressin affects kidneys

Question 15

What is Oxytocin with regards to peptide love?

Answer 15

Peptide of love
Milk ejection
Uterine contractions
Monogamous bonding
There are oxytocins released from they hypothalamus to other parts of the brain. CNS -> olfactory bulb, reward centres of the brain, amygdala, lateral septum, etc

Question 16

What are the mechanisms of oxytocin?

Answer 16

During labour, when the head pushes against the uterus, causes stretching. This means the various neurones projecting from the uterus to the hypothalamus gets activated and releases oxytocin into the blood circulation. This stimulates the uterus to contract. As the babies head moves forward, it stimulates the placenta to make prostaglandins, which stimulates more contractions. This leads to a positive feedback of producing more oxytocins leading to increased contractions. The estradiol released from the ovaries plat a role in activating oxytocin receptors on the uterus.

Question 17

What are the CNS effects of oxytocin?

Answer 17

Antidepressant
Hypnotic
Treatment of autism
Induces Trust
Social cognition
Anxiolytic
Antipsychotic
Anti-OCD

Question 18

What are the cellular and molecular mechanisms of neurohormones?

Answer 18

The mechanism of action depends on the classes of the hormones and their receptors.

Peptide and protein hormones bind to surface receptors and activate intracellular signalling mechanisms that result in alteration of target protein and/or enzyme activities.

Binding of insulin and growth hormone to its cell surface receptors leads to dimerisation of the receptors, subsequently recruiting tyrosine kinases (e.g. JAK2 or MAPK) which phosphorylate target protein (e.g. STAT) to induce biological responses.

Mutations in the GH receptor gene can result in defective hormone binding or reduced efficiency of receptor dimerisation -> GH resistance
“Laron syndrome”

Question 19

What is the G-protein/adenylate cyclase pathway?

Answer 19

The G-protein/ adenylate cyclase pathway:
G-protein coupled receptors (GPCRs) are the largest of the cell surface receptor groups with over 140 members. This receptor has unique 7 transmembrane domains. Binding of hormone to GPCR results in conformational changes in the receptor, leading to GTP exchange for GDP and catalytic activation of adenylate cyclase.

TSH and ACTH bind to cell surface GPCR receptors and activate G-proteins that stimulate or inhibit adenylate cyclase. Stimulation of adenylate cyclase increases intracellular cAMP levels, that activate protein kinase A which phosphorvlates target proteins (e.g. CREB) to initiate specific gene expressions and biological responses.

Transcriptional activation of genes with CRE
Activating mutations of TSH receptor -> thyroid adenomas “constitutive

Question 20

What is the DAG/IP3 pathway?

Answer 20

The DAG/IP3 pathway:
Oxvtocin and GnRH bind to cell surface GPCRs and stimulate phospholipase C. It converts phosphatidylinositol bisphosphate
(PIP2) into inositol triphosphate
(IP3) and diacyglycerol (DAG). IP3 stimulates Ca2+ release from intracellular stores, particularly the endoplasmic reticulum. DAG activates PKC. These stimulate the phosphorylation of proteins and alter enzyme activities to initiate a biological response.

Loss-of-function mutations in GnRHR
-> Sex hormone deficiency & delayed puberty (hypogonadotrophic hypogonadism)

Question 21

What are the cytoplasmic/nuclear receptors?

Answer 21

Cytoplasmic/nuclear receptors:
Steroid and thyroid hormones can diffuse across the plasma membrane of target cells and bind to intracellular receptors in the cytoplasm or the nucleus.

These receptors function as hormone-regulated transcription
factors, controlling gene expression.
Nuclear receptors commonly share a transcriptional activation domain (AF1), a Zn2+ finger DNA binding domain and a ligand (hormone) binding/dimerisation domain.

1) Steroid hormone (S) passes through plasm membrane.
2) Inside target cell, steroid hormone binds to a specific receptor protein in cytoplasm or nucleus
3) Receptor/steroid
 hormone complex ent the nucleus and binds DNA, causing gene transcription.
4) Protein synthesisis induced.
5) Protein is produced.

There are more than 150 members of receptor proteins, majority of which are “orphan” receptors.

Question 22

What are the disorders of neurohormone production?

Answer 22

Pituitary adenoma
Loss of visual field (pressure on optic nerve)
Too much GH (Gigantism & Acromegaly)
Too much ACTH excess cortisol secretion (Cushing syndrome)
Too much PRL (Hyperprolactinaemia)
Hypopituitarism (reduced pituitary function)
Hypogonadism & infertility

Question 23

What happens if this regulation goes wrong
either hypo or hyperthyroidism occurs?

Answer 23

Hypothyroidism occurs if there is too little
thyroid hormone.
This disease affects 1 in 4000 infants. If left
untreated, it can cause mental retardation,
slow growth, cold hands and feet, and lack
of energy among other things.
The most common cause is Hashimoto’s disease an
autoimmune disease in which the immune system makes antibodies to the thyroid. It is seen more often
in women and those with a family history of
thyroid disease.
In older people it may follow radioactive iodine treatment, thyroid surgery or pituitary dysfunction; sometimes with goitre, heart failure, depression and slowed mental functioning, myxedema, birth defects. Babies may be stillborn or premature with lower IQ in later in life.
The brain mechanisms underlying these changes in function are not well understood.

Thyroxine controls basal metabolic rate:
Too little = Decrease bmr = weight gain

Question 24

What happens when there is too much thyroxine?

Answer 24

The opposite of this is Hyperthyroidism or Graves’ disease

Cause
Graves’ disease is also an autoimmune disease.
Antibodies attack the thyroid gland and mimic
TSH so the gland make too much thyroid hormone (hyperthyroidism).
It often occurs in women (20 – 50; with a family history of thyroid disease).

Signs and Symptoms
Goitre (enlarged thyroid gland) ,Difficulty breathing, Anxiety, irritability,difficulty sleeping,
fatigue, Rapid or irregular heartbeat, trembling fingers, Excess perspiration, heat
sensitivity, Weight loss, despite normal food intake

Complications
heart failure, osteoporosis. Pregnant women with uncontrolled Graves’ disease are at
greater risk of miscarriage, premature birth, and babies with low birth weight.
Graves’ ophthalmopathy (occurs if untreated; bulging eyes, relatively rare)

Question 25

What problems could arise with regulation of cortisol?

Answer 25

Once again there are 2 aspects of Adrenal pathology, Adrenal insufficiency (Addison’s disease) and excessive secretion (Cushing’s syndrome).Adrenal insufficiency (AI) occurs when the adrenals do not secrete enough steroids.

Cause
The most common cause of primary AI is autoimmune,

Symptoms
Symptoms include fatigue, muscle weakness, decreased appetite, and weight loss, nausea, vomiting, and diarrhea, muscle and joint pain, low blood pressure, dizziness, low blood glucose, sweating,
darkened skin on the face, neck, and back of the hands and irregular menstruation.

Cushing’s syndrome result from having excess
cortisol secretion

Exogenous Cushing’s syndrome occurs in
Patients Taking cortisol-like medications such as
Prednisone for the treatment of inflammatory
disorders eg asthma and Rheumatoid arthritis
or after organ transplant.
It can also occur with pituitary tumors produces too
much ACTH (Cushing’s disease). Signs and symptoms of Cushing’s syndrome include. Weight gain, rounded face and extra fat on the upper back and above the clavicles, diabetes, hypertension, osteoporosis, muscle loss and weakness, thin, fragile skin that
bruises easily, purple-red stretch marks, facial hair in women, irregular menstruation,.