Physiology week 3 all - feedback loops

homeostasis

steady internal physical and chemical conditions

types of feedback loop

direct, first order, second order, third order

Control points

points in the feedback loop when negative feedback can supress further synthesis/secretion of hormones

Direct feedback loop

one control point. When a gland is stimulated to synthesise/secrete hormones, the target organ responds by decreasing the amount of stimulus being produced

atrial natriuretic peptide (ANP)

mammalian direct feedback loop. Stretched atria stimulate atrial cardiomyocytes to secrete more ANP . ANP acts on kidneys to increase Na+ loss in urea. loss of water and na+ decreases atria stretching plasma,

second/third order feedback loop

either one or two endocrine glands introduced between integrator and target organ. - these interacting glands are called an endocrine axis.

Second order feedback loop

a variable is detected by a sensor and relays a signal to the integrator via sensory neurone. Integrator sends signal to endocrine gland. endocrine gland acts on effector cells in target organ. Target organ responds by lowering stimulus to sensory neurone and negative feedback to endocrine gland preventing further hormone secretion,

Third order feedback loop

sensor → integrator - > intermediate endocrine gland → secondary intermediate endocrine gland → effector cells. effector cells exert negative feedback at three control points.

Hypothalamo-pituitary complex

third order feedback loop. intermediate endocrine glands : hypothalamus, pituitary gland. target organ also endocrine gland e.g. adrenal, gonadal, thyroid

Hypothalamus

this collection of neurones forms clusters called hypothalamic nuclei bellow the thalamus. it is in a part of the brain called diencephalon, and is connected to the pituitary gland via a narrow stalk called the infundibulum

pituitary gland

has two lobes - posterior pituitary and anterior pituitary

posterior pituitary

also known as neurohypophysis. formed by an outgrowth of neural tissue from the hypothalamus

anterior pituitary

growth of glandular epithelial tissue from the roof of the buccal cavity.

endocrine cells of the anterior pituitary

corticotropes, gonadotropes, lactotropes, somatotropes, thyrotropes

impact of embryonic origins on posterior lobe//neurohypophysis

magnocellular neurones in hypothalamus have axons spanning down to the lobe along the hypothalamo-hypophyseal tract allowing neurohypophyseal hormones from the hypothalamus to be secreted from pituitary gland.

Impact of embryonic origins on anterior lobe/adenohypophysis

connected to hypothalamus through hypothalamo-hypophyseal portal circulation. this starts in the median eminence (third ventricle of the brain) and ends draining into the lobe. peptide hormones and neurotransmitters from hypothalamic parvicellular neurones secreted.

hypophysiotropic hormones

almost all peptides, secreted by neurosecretory cells, dopamine (neurotransmitter) TRH, CRH, GHRH, GHIH, GnRH

dopamine

→ lactotropes → prolactin → breasts

TRH

→ thyrotropes → thyroid stimulating hormone→ thyroid gland → thyroxine etc

CRH

→ corticotropes → ACTH → adrenal cortex → cortisol

GHRH and GHIH (somatostatin)

→ somatotropes → GH → liver → somatomedins (IGFs)

GnRH

→ gonadotropes → LH/FSH → Gonads. LH = Female → estrogens, progesterone FSH = male → androgens

Releasing hormones

stimulate synthesis and secretion of peptide/protein/glycoprotein hormones from anterior pituitary.

prolactin PRL

stimulate lactation in breasts

ACTH

adrenocorticotropic hormone - cortisol - elevate plasma glucose conc, trigger cell differentiation, promote development of secondary sexual characteristics

GH

growth hormone -indirect, or direct, IGF-1

FSH

follicle stimulating hormone - estradiol , promote second sexual characteristics, female.

LH

luteinising hormone - progesterone and testosterone. triggers ovulation , regulate female sexual receptivity

long loop negative feedback

end organ hormone exerts negative feedback to supress hypothallamic hormone

short loop negative feedback

feedback loop from anterior pituitary to hypothalamus

Diurnal/circadian rhythm

feedback loops cause a rhythm over a 24 hour period,

How plasma concentrations affects circadian rhythm

cortisol conc highest upon waking. falls to a nadir in late evening/early night. this allows high glucose levels when mammals need to be most active (this is shifted by 12 hours if nocturnal)

How feedback loops affect plasma glucose

as cortisol conc peaks long loop feedback is exerted on CRH and ACTH causing conc to falll and reach a nadir at niight. at night with minimal concentrations, levels rise again until morning peak. chronic stress reduces negative feedback causing distruption to sleep

Neuroendocrine reflexes

neuroendocrine cells release small neuropeptide hormones into circulation instead of neurotransmitters (pituitary gland)

Tropic hormone

hormone targeting other endocrine cells

Vasopressin and oxytocin

Posterior pituitary nonapeptide hormones. Lariat structure with covalent disulfide bond

Lariat structure

lasso

Oxytocin OT

induces contraction of smooth muscle in the uterus. OT receptor is a gpcr. the Gq alpha subunit couples with phospholipase C, activating inositol triphosphate pathway, and increasing intracellular calcium

AVP vasopressin

antidiuretic hormone, facilitating water resorption in the distal nephrons and collecting ducts of the kidneys) and as a vasopressor (inducing the contraction of vascular smooth muscle cells to increase vascular resistance and hence raise blood pressure).

transcription and translation of nonapeptides

transcribed and translated in the cell bodies of magnocellular neurones located in the supraoptic, ventromedial and / or paraventricular nuclei (hypothalamus).packaged into secretory vesicles

secretion of nonapeptides

transported along the cytoskeleton along axons from cell bodies in the hypothalamus to the axonal terminals in the posterior pituitary gland / neurohypophysis.  secretion of the neurohypophyseal hormones regulated by neuroendocrine reflexes

fergusson reflex

sensory inputs from the distended cervix trigger increased secretion of OT that stimulates myometrial contractions which further distend the cervix.  This positive feedback spiral minimises the time that the infant spends in the birth canal.

milk ejection reflex

stretching of the nipple and surrounding areola sends a sensory input to increase secretion of OT that stimulates contraction of the lobulo-alveolar ducts in the mammary gland, promoting increased milk ejection for the infant.

fight or flight response

in the medulla of the adrenal gland. fright increases stimulation of the adrenal medulla by the sympathetic branch of the autonomic nervous system.  chromaffin cells of the adrenal medulla increase synthesis and secretion of the catecholamine hormone, adrenaline.  adrenaline increases the mobilisation of glucose stores, increasing cardiac output (by increasing heart rate) and suppressing any non-vital physiological processes.

 

First order instead of direct feedback

first order system senses the stimulus via sense organ and transmitted to integrating centre. signal is measured and acted upon if it reaches a specific threshold. still only a single control point.

HPT axis as a third order feedback system

Hypothalamus creates thyrotropin releasing hormone TRH (peptide hormone). TRH stimulates thryrotropes in anterior pituitary to create thyroid stimulationg hormoone TSH → Thyroid which metabolises thyroglobulin which produces T3 and T4. → anterior pituitary, hypothalamus, stimulus.

THyroglobulin

large peptide, tyrosine modules, metabolised by adding 1 or 2 iodine. 2 tyrosine modules are added together to create T3 or T4 depending if you join monoidotyrosine or di-idotyrosine.

Adrenal gland

ad-renal (on top of kidney). outer cortex makes corticoid steroid hormones. inner medulla (made of chromaffin cells) makes catecholamines (adrenaline).

Neural crest derived

cells similar to neurons which can migrate through the membrane. they have neural identity allowing them to make neurotransmitters.

layers of the adrenal gland

Capsule, Zona glomuerulosa, zona fasiculata

capsule

outer layer of the adrenal gland, structural integrity.

Zona glomerulosa

stimulated by electrolytes by measuring potassium ions directly and sodium ions indirectly to make mineralocorticoids such as aldosterone. Aldosterone causes reabsorbtion of sodium ions and by proxy water. this increases blood plasma volume and blood pressure. potassium ions are lost in exchange.

Renin angiotensin aldosterone system

A fall in blood volume or pressure causes less sodium sensed by kidney. Increased conversion of prorenin to renin (enzyme) → blood. Renin converts angiotensinogen to angiotensin 1 (hormone), causing blood vessels to constrict and increase blood pressure. Angiotensin 1 → angiotensin 2 by angiotensin conversion enzyme (ACE). AT2 binding to AT2 receptor in ZG stimulate aldosterone synthesis in adrenal gland. → rise in blood volume and pressure.

Zona fasciculata

stimulated by ACTH so that adrenal gland synthesises glucocorticoids e.g. cortisol, increasing blood plasma glucose concentration and non essential fatty acids. (chronic stress response) and can inhibit non essential activity and immune system. .

Cortisol

activated in adrenal gland by ACTH. circulates bound to albumin or cortisol binding globulin. Negative feedback on cortisol releasing hormone in hypothalamus and ACTH in pituitary gland and metabolic input in hypothalamus (reducing chronic stress) .

HPA axis

hypothalamus → cortisol releasing hormone → acth → cortisol → anterior pituitary and hypothalamus and chronic stress (third order)

Zona reticularis

stimulated by ACTH. produces adrenal androgens e.g. DHEA. DHEA metabolissed in adrenal but metabolised to testosterone and estrogen in other tissues. associated with puberty onset and aging. circulates bound to allbumin or SHBG (sex hormone binding globulin. If DHEA is sulfated it is water soluble so doesnnt bind to albumin.

medulla

modified sympathetic autonomic nervous system made of chromaffin cells (modified neurons no axons) . produces catecholamines (noradrenaline, adrenaline) which is stored in granules. sympathetic neural input causes adrenaline release into blood (not endocrine controlled)

Adrenaline/epinephrine → Noradrenaline

noradrenaline is converted to adrenaline by pnmt enzyme methylation. this is because pnmt is upregulated by glucocorticoid hormones which are highest in the adrenal gland.

Adrenaline response receptors

GPCR receptors, alpha receptor - increase intracellular calcium conc, beta receptor - adenylyl cyclase action.

Acute stress response

a receptor: increase blood flow, blood pressure, heart rate. b receptor: increase blood glucose concentration

sensitisation of CNS - pupil dilation, sweating

glycogen

polymer of glucose - energy store

glucagon

hormone, converts glycogen to glucose via gpcr receptor.

insulin

convert glucose to glygogen via enzyme linked receptor

regulation of blood glucose (locations)

glucose < - > glycogen in liver. pancreas creates insulin and glucagon. → liver

Pancreas and digestive enzymes

in centre of abdomen, produces digestive enzymes in acinus cells which flow via ducts creating calcium carbonate to maintain alkaline environment

pancreas, islet of langerhans

alpha cells secrete glucagon, beta cells produce insulin, delta cell produce somatostatin which suppresses them both. pancreatic polypeptide produced by pp cells regulating appetite

blood glucose

4-8 mmol/litre. if too little hypoglycaemia - brain function damage. if too much - hyperglycaemia - change osmolarity increasing water retention. glucose sticks to lipids and proteins causing kidney nerve and capillary damage.

anabolic state

polymer synthesis is driven by insulin

Catabolic state

polymer breakdown driven by glucagon

blood glucose regulation

blood glucose rises → alpha cells repressed, less glucagon, less glucose. at same time beta cells activated - more insulin, more glycogen. blood glucose falls - opposite. can work simultaneously,, a little bit etc.

how beta cells sense and respond to glucose

beta cells: membrane channels. ATP sensitive potassium channel - closed when atp bound. and voltage gated calcium channel open when cell is de-polarised. Glucose transported in by GLUT 2 transporter. Glucokinase convert glucose to Glucose - 6- phosphate creating internal conc fall → more glucose in. Glucose 6 phosphate used in glycolysis creating atp. atp binds to k channel. k cant leave cell. cell depolarises. ca+ opens and calcium flows in causing insulin granule exocytosis.

what beta cell responds to

blood glucose conc, food intake ( produces gastrointestinal hormone incretins increasing insulin production and parasynthetic stimulation) , blood amino concentration increases beta cell activity and creating more insulin. Adrenaline suppreses beta cells so glucose is available to fight/flight.

How cell responds to insulin

TKA receptor -. cascade → GLUT 4 exocytosis into membrane → glucose entry and storage.

What defines a hormone

Secreted by an endocrine gland, travels in the circulatory system

Why is the endocrine system necessary

signalling is more stable and has more long lasting effects.

Integrating Center

Region in the hypothalamus which receives and processes a signal from a sensor and produces a response.

Oxytocin Positive feedback

contraction -> stretch sensitive neurones in cervix pressed against. -> signal to posterior pituitary -> hypothalamus has produced oxytocin and stores in pituitary. pituitary signalled to release oxytocin. oxytcin causes greater contraction of uterine muscles -> more oxytoxin. When the stimulus is removed oxytocin production and therefore contractions slow.