BIOM*3200 Midterm 2

claude bernard

father of modern physiology; said that our internal environment remains remarkably constant despite changes in the external milieu

walter cannon

coined the term homeostasis to describe the relative stability of the internal environment

components of homeostatic systems

• negative feedback: shift in physiological variable outside normal range

• sensor: detects shift

• integration/control centre: sets normal range and coordinates the next set of events

• response system: changes environment to get back to set point

blood pressure homeostasis

1. blood is evenly distributed throughout the body when lying flat

2. when standing, blood pools in legs

3. pooling blood causes reduction in venous return and therefore cardiac output, so pressure falls

4. drop in blood pressure is detected by baroreceptors in the aortic arch and carotid sinus

5. the baroreceptors respond by increasing sympathetic and reducing parasympathetic outflow

6. peripheral vascular resistance is increased, which causes venous return, cardiac output, and blood pressure to increase

major regulatory systems to maintain homeostasis

skin, cardiovascular, renal, digestive, respiratory, musculo-skeletal

major regulated factors for homeostasis

water, electrolytes/pH, nitrogenous compounds, oxygen, carbon dioxide, temperature, toxicants

endocrine dysfunctions

• hyper-function: too much hormone

• hypo-function: too little hormone

• resistance: too little effect

endocrine gland

a tissue which releases a substance into the bloodstream; this substance then travels via the blood to influence a target cell

classic minkowsi experiment

surgically removed the pancreas in the dog; the dog developed symptoms of diabetes; implanting pieces of pancreas under the skin prevented symptoms of diabetes

banting and best

the discovery of insulin; identified antidiabetic substance in pancreatic extracts; injected extracts prevents symptoms of diabetes

insulin

peptide hormone produced by beta cells of the pancreas; promotes absorption of glucose from blood to skeletal muscle and fat tissue; stored in inactive form as a hexamer of zinc ions and histidine residues

what makes a chemical a hormone?

proteins and polypeptides; steroids (cholesterol derivatives), glycoproteins; amines (catecholamines or thyroid)

autocrine hormones

a cell responds to a signal it secreted

paracrine hormones

the hormone acts on a cell nearby; doesn’t enter the bloodstream

endocrine hormones

hormone is released into the blood by an endocrine gland to reach the target; long distance

mode of secretion of peptide hormones: synthesis, storage, release from cell, transport in blood, half life, example

• synthesis: in advance

• storage: secretory vesicles

• release from cell: exocytosis

• transport in blood: dissolved in plasma

• half life: short

• example: insulin

mode of secretion of steroid hormones: synthesis, release from cell, transport in blood, half life, example

• synthesis: on demand

• release from cell: diffusion

• transport in blood: bound to carrier proteins

• half life: long

• example: estrogen, androgen

mode of secretion of catecholamine hormones: synthesis, storage, release from cell, transport in blood, half life, example

• synthesis: in advance

• storage: secretory vesicles

• release from cell: exocytosis

• transport in blood: dissolved in plasma

• half life: short

• example: epinephrine, norepinephrine

mode of secretion of amine thyroid hormones: synthesis, storage, release from cell, transport in blood, half life, example

• synthesis: in advance

• storage: secretory vesicles

• release from cell: diffusion

• transport in blood: bound to carrier proteins

• half life: long

• example: thyroxine T4

overview of receptor binding

hormones bind to receptors in target cells; very high specificity for a particular hormone; continuous turn-over of receptor-hormone complex; receptors for most hormones are found in the plasma membrane of target cells; receptors for thyroid and steroid hormones are inside the target cells

transmembrane receptors

hormone binds to the extracellular domain of the receptor and activates one or more cytoplasmic signaling pathways, usually involving phosphorylation and enzyme activation; some lead to gene expression responses, others have local effect in target cell

adenylate cyclase pathway

1. hormone binds to receptor and the G-proteins dissociate

2. alpha subunit activates AC

3. catalyzes product of cAMP

4. removes regulatory unit from PKA

5. PKA activates other molecules for hormonal response

epinephrine and adenylate cyclase

1. epinephrine binds to B-adrenergic receptor on liver cell

2. G-proteins activated, subunit carrying GDP dissociates, GTP binds

3. subunit activates adenylyl cyclase which catalyzes ATP to cAMP

4. cAMP activates PKA, which activates phosphorylase

5. phosphorylase converts glycogen to G6P

6. G6P is turned into glucose in the liver

robert lefkowitz and brian kobilka

received nobel prize by determining how GPCRs work to understand network of signaling between cells; how cells sense their environments

phospholipase C-Ca²⁺ pathways

1. hormone binds to receptor, G proteins dissociate

2. activates phospholipase C (PLC)

3. causes breakdown of membrane phospholipid to IP3

4. IP3 binds to endoplasmic reticulum

5. release of stored Ca2+ into cytoplasm

6. Ca2+ activates other molecules

alpha vs. beta adrenergic receptors

alpha-adrenergic receptors activate phospholipase C via Gq; beta-adrenergic receptors activate adenylate cyclase via Gs

steroid hormone receptors process when hormone binds

1. steroid hormone transported bound to plasma carrier protein

2. steroid hormone binds cell cytoplasm receptor

3. translocates to nucleus, binds to DNA

4. acts as a TF to stimulate gene transcription

5. protein products produce response

thyroid hormone receptor process when hormone binds

1. thyroxine (T4) binds to carrier binding protein

2. T4 is converted to triiodothyronine (T3)

3. T3 uses binding proteins to enter nucleus

4. hormone-receptor complex binds DNA

5. new mRNA and proteins produced

pituitary gland

physically connected to hypothalamus through an infundibulum (stalk); whole gland protected by bone; anterior pituitary (adenohypophysis) acts as an endocrine gland, posterior pituitary (neurohypophysis) acts as extension of neural tissue

hypothalamic hormones/factors

dopamine, prolactin releasing hormone, thyrotropin-releasing hormone, corticotropin-releasing hormone, somatostatin, growth hormone releasing hormone, gonadotropin-releasing hormone

dopamine

PIH; inhibits secretion of prolactin

prolactin releasing hormone (PRH)

stimulates release of prolactin

thyrotropin-releasing hormone (TRH)

regulates secretion of thyroid stimulating hormone (TSH)

corticotropin-releasing hormone (CRH)

regulates secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary

somatostatin

GHIH; inhibits secretion of growth hormone

gonadotropin-releasing hormone (GnRH)

regulates secretion of gonadotropin-releasing hormones, luteinizing hormone (LH), and follicle stimulating hormone (FSH)

CRH synthesis and inhibition

• central stimulatory control: noradrenergic; stimulates pre-proCRH gene and protein expression (196 AA), processed to CRH (41 AA); stimulates pulsatile release of CRH

• inhibitory influences: physiological levels of cortisol inhibit release of CRH

CRH production and release

produced by parvocellular neuroendocrine cells within paraventricular nucleus of hypothalamus; released at median eminence (base of brain) from neurosecretory nerve terminals, into blood vessels in the hypothalamic-pituitary portal systems

hypothalamic-pituitary-adrenal (HPA) axis

controls the body’s stress response

1. in response to stress, the hypothalamus releases CRH into bloodstream

2. CRH stimulates the anterior pituitary corticotropes to release ACTH and produce POMC

3. ACTH activates the adrenal cortex to produce glucocorticoids such as cortisol

4. glucocorticoids regulate activity of HPA axis through negative feedback

phases of HPA axis dysregulation

• acute phase: after acute stress, there is resistance and attempted adaptation

• compensatory phase: as chronic stress predominates, there is attempted adaptation

• exhaustion phase: failed adaptation

the adrenal glands

made up of two embryologically distinct tissues that merged during development; adrenal cortex and adrenal medulla

adrenal cortex

secretes steroids/corticosteroids; glucosteroids controlled by ACTH, mineralocorticoids (eg. aldosterone) controlled by renin-angiotensin system; sex steroids controlled by ACTH

proopiomelanocortin (POMC) family

• ACTH: adrenocorticotropic hormone; regulates adrenal cortex function

• MSH: melanocyte stimulating hormone; skin pigmentation in response to UV radiation

• End: B-endorphin; analgesic roles in CNS

• Enk: enkephalin; analgesic roles in fetus

• MC3,4,5- receptors: hypothermia, hypotension, feeding behaviour, appetite

convertases

enzymes that cleave POMC; different convertases give rise to different products

adrenal gland structure: outside layers to in and hormones produced

capsule; zona glomerulosa produces mineralcorticoids; zona fasciculata produces glucocorticoids; zona reticularis produces androgens; medulla produces epinephrine

functions of cortisol

protects against hypoglycemia; promotes gluconeogenesis to increase blood sugar; suppresses immune system and regulates inflammatory response; causes breakdown of skeletal muscle for gluconeogenesis; causes bone catabolism; affects brain function (mood, memory, learning)

cushing’s syndrome

primary hypercortisolism; prolonged exposure to high levels of cortisol; can be caused by taking glucocorticoid drugs or by diseases that result in excess cortisol, ACTH, or CRH; causes changes in carbohydrate and protein metabolism, hyperglycemia, hypertension, muscular weakness; metabolic problems give rise to puffy appearance, CNS disorders such as depression, decreased learning and memory

cushing’s disease

secondary hypercortisolism; pituitary-dependent; a tumour in the pituitary gland produces large amounts of ACTH, causing adrenals to make excess cortisol

treatment for cushing’s disease and syndrome

surgery to remove pituitary or adrenal gland; medical management of signs and symptoms (insulin for diabetes, anti-hypertensives for BP); if not treated, disease worsens and overall health deteriorates and could lead to stroke or myocardial infarction

addison’s disease

primary hypocortisolism; adrenal insufficiency; many causes, may be from genetics, autoimmune destruction of adrenal cortex; can be acquired due to high-dose steroids given for >1 week which suppress CRH and ACTH and adrenal glands; symptoms include hair loss, blurry vision, abdominal pain, decreased appetite, darkening of skin, shaking, tremors, depression

secretion patterns of adrenal cortisol

continuous, pulsatile, circadian release; peaks at post-waking; lowest in the evening

pituitary pars intermedia dysfunction (PPID)

affects older horses but has been diagnosed as young as 10 years old; caused by impaired pituitary (hyperplasia and hypertrophy of pars intermedia); leads to increased secretion of cortisol by adrenal glands; results in high blood glucose and suppression of immune system

common signs of pituitary pars intermedia dysfunction (PPID)

hypertrichosis (excessive hair growth); patches of long hair on legs, wavy hair on neck, changes in coat colour; muscle atrophy; excessive sweating; formation of fat pads on top of neck, tail head, and above or around eyes; pot-bellied appearance

diagnosis and treatment of pituitary pars intermedia dysfunction (PPID)

diagnose by measuring basal ACTH and fasting insulin; treatment with medication that acts on pituitary gland to decrease circulating ACTH (eg. pergolide); manage with exercise, weight loss, limiting starch and sugar in diet

thyroid gland

just below larynx on either side of trachea; lateral to the first 3-8 tracheal rings; 2 lobes connected by isthmus which is fibrous in cows and horses, indistinct in dogs and cats; largest purely endocrine gland

thyroglobulin

long peptide chain with lots of tyrosine side chains; found in colloid; made by follicular cells; thyroid peroxidase enzyme helps attach iodide to tyrosine residues

thyroid hormone synthesis

1. iodide is brought from the blood into follicular cells by sodium-iodide transporter, then into colloid by pendrin (transporter)

2. TPO removes an electron from iodide to produce iodine

3. iodine binds tyrosine residues in thyroglobulin to produce MIT or DIT

4. enzymes in the colloid modify the structures of MIT and DIT, joining them to produce T3 and T4

5. upon stimulation from TSH, thyroglobulin is taken up by follicular cells and cut, separating T3 and T4

6. T3 and T4 secreted out to bloodstream bound to carrier protein

MIT and DIT production and modifications

• attachment of 1 iodine on a tyrosine ring produces monoiodotyrosine

• attachment of 2 iodines on a tyrosine ring produces diiodotyrosine

• MIT + DIT produces triiodothyronine (T3)

• DIT + DIT produces tetraiodothyronine (T4)

thyroid hormone transport

99% of thyroid hormones in blood circulation bound to plasma carrier protein thyroxin-binding globulin (TBG); some are biologically active and must lose carrier protein to elicit effects in target cells

circadian rhythm of thyroid hormones

secretion highest in humans between 10am and 2pm; elevate basal metabolic rate; secretion highest in rodents at night instead of during the day

patterns and regulation of TRH secretion

pulsed secretion from hypothalamus; young animals secrete more than older animals; stress and cold result in increased secretion

physiological action of thyroid hormones

elevate basal metabolic rate; normal gonadal development and function; normal embryonic/fetal development, particularly development of CNS; production impaired with age

hypothyroidism

abnormally low basal metabolic rate; weight gain, lethargy, intolerance to cold

hyperthyroidism

increased basal metabolic rate; weight loss, muscular weakness, nervousness, protruding eyes (exophtalmos)

causes of hypothyroidism and hyperthyroidism

insufficient dietary iodide; thyroid gland defect; impaired thyroid hormone pathway; insufficient TSH from anterior pituitary; insufficient TRH from hypothalamus; mutant TSH or TRH receptors (genetic); mutant TH transport proteins; autoimmunity

cretinism

congenital deficiency of thyroid hormones; usually due to innate maternal hypothyroidism or iodine deficiency; reduced physical growth and development delays; treatment with thyroxin (T4) soon after birth (<1 month of age) completely or almost completely restores mental development by age 5

terminal brain differentiation of thyroid hormones

thyroid hormone-dependent brain development begins in utero and is completed after birth; important for dendritic and axonal growth, myelin formation, synapse formation, neuronal migration; maternal thyroid hormones first supply needs of the embryo/fetus

goiters pathophysiology

abnormal thyroid growth due to hypothyroidism

1. low iodide intake results in low thyroid hormone production

2. low plasma thyroid hormones results in high TRH

3. high TRH results in high plasma TSH

4. high plasma TSH stimulates excess growth of thyroid

graves disease

due to hyperthyroidism; autoimmune antibodies activate thyroid gland, leading to high plasma T3 and T4; high thyroid hormone concentration leads to low TRH and low plasma TSH; exophthalmia (protruding eyes)

symptoms of hyperthyroidism in cats

weight loss despite increased appetite; increased thirst; increased urination; increased heart rate; vomiting; diarrhea; restlessness; hyperactivity; greasy or matted hair

primary hypothyroidism in dogs

usually from destruction of thyroid; lymphocytic thyroiditis (immune infiltration) affects 50% doberman pinschers; idiopathic atrophy of thyroid (thyroid tissue lost and replaced by adipose cells); predisposed breeds are doberman pinschers, golden retriever, irish setter, miniature schnauzer, dachshund, cocker spaniel, airedale terrier

secondary hypothyroidism in dogs

• thyroid destruction secondary to neoplasia affects 40% of dogs with cancer

• congenital hypothyroidism/cretinism/pituitary dwarfism

• 75% of both lobes must be non-functional before developing clinical signs

• myxedema (swelling of tissues with severe hypothyroidism), stupor, coma

thyroid disorder treatments

surgery (hemithyroidectomy), hormone supplementation, radiation therapy (for cancer), blockers (thiouracil derivates and thiocarbamides decreases iodination and conversion from T4 to T3); stimulants (furosemide increases conversion from T4 to T3); diet, electrolyte infusions

natural vs. synthetic thyroid hormone medication

• synthetic formulations contain only T4 which must be converted to T3 by the body for it to work; by the de-iodinase enzyme; may add cytomel (T3) in addition to synthroid (T4)

• natural is preferred because synthetic lacks T2, T1, and calcitonin

• supplementing with calcitonin helps

calcitonin production after total thyroidectomy

may be deficient or absent in patients because total thyroidectomy removes C cells (parafollicular cells)

locations of calcium

• 99% found in bones stored as hydroxyapatite made of calcium salts and phosphate provide structural integrity

• 1% in soft tissues: intracellular 0.9% and extracellular 0.1%; essential for several normal biochemical processes

extracellular calcium

very tightly regulated; 50% ionized; 40% protein-bound; 10% complexed with phosphate and citrate; in extracellular fluid and bone

intracellular plasma

very tightly regulated; more abundant than extracellular; largely associated with membranes in mitochondria, endoplasmic reticulum, plasma membrane

total body calcium formula

• intake - output

• intake from the diet: 1/3 absorbed in small intestine; absorption is hormone regulated; recommended 1000 mg/day

• output: kidneys

3 hormones that regulate movement of calcium between bone, kidneys, and intestine

parathyroid hormone (PTH), calcitriol (vitamin D3), calcitonin

parathyroid hormone

a peptide made by parathyroid gland; secreted continuously; not stored; helps regulate calcium

parathyroid gland

essential for life; seen in terrestrial amphibians onwards; 2 cell types within

two cell types in the parathyroid gland

chief cells that produce PTH; oxyphils

3 mechanisms to raise blood Ca²⁺ via PTH

1. stimulates osteoclasts to resorb bone

2. stimulates kidneys to resorb Ca²⁺

3. stimulates kidneys to produce enzyme needed to activate vitamin D, which promotes better absorption of Ca2⁺ from food/drink across intestinal epithelium

hypocalcaemia

low blood calcium; PTH secretion increases

hypercalcaemia

high blood calcium; decrease PTH secretion

bone deposition

by osteoblasts; secrete a matrix of collagen protein, which becomes hardened by deposits of hydroxyapatite

bone resorption

by osteoclasts; dissolves hydroxyapatite and return the bone Ca2+ and phosphate to the blood

calcium in bone; bone structure

bone is constantly formed and resorbed; contains calcified ECM that forms when calcium phosphate crystals precipitate and attach to a lattice support; calcium in bone is mainly in hydroxyapatite crystal form, but a small fraction is ionized and readily available

low blood calcium: process to bring back to normal

parathyroid gland increases PTH secretion; PTH stimulates kidneys to resorb calcium and produce 1-alpha-hydroxylase enzyme needed to activate vitamin D; vitamin D3 will act on intestines to absorb more calcium from food/drink; also stimulates bone resorption

vitamin D synthesis

1. vitamin D3 is produced from its precursor 7-dehydrocholesterol under the influence of UVB sunlight

2. inactive vitamin D3 secreted into blood from skin/intestine

3. goes to liver and has a hydroxyl group added to C25

4. requires hydroxyl group addition to C1 to become active; done by enzyme in kidneys stimulated by PTH)

vitamin D function

stimulates intestinal absorption of calcium; directly stimulates bone resorption by promoting formation of osteoclasts

sources of vitamin D

production of vitamin D in the skin; food sources (milk, eggs, fish); exposure to sunlight; people in northern/southern latitudes have to ingest it through diet or supplements

calcitonin

made in C cells of thyroid in response to high calcium; thought to only play a minor role in adult humans because thyroidectomy patients are not hypercalcaemic

high blood calcium: process to bring back to normal

1. thyroid gland increases calcitonin secretion

2. calcitonin acts on the kidney to stimulate excretion of calcium in urine

3. acts on the small intestine to decrease calcium absorption

4. inhibits osteoclast activity for less bone resorption

phosphate metabolism

controlled by the same mechanisms that regulate calcium metabolism to return or receive phosphate to/from bone, kidney filtrate, and GI tract

hyperparathyroidism

parathyroid too active; hypercalcaemia; increased bone resorption causing fractures; mineralization of soft tissues; increased thirst and urination because calcium blocks ADH effects

hypoparathyroidism

parathyroid not active enough; hypocalcaemia; muscular weakness; ataxia; cardiac arrhythmias

vitamin D deficiency

results in poor bone mineralization; in children, causes rickets with bone pain, stunted growth, deformities; in adults, causes osteomalacia with bone pain and fractures

osteoporosis

most common disorder of bone; reduction of bone quality due to excess absorption; risk of bone fractures; risk factors are sex (females after menopause), lack of exercise, calcium deficient diet