PSL300 - Term test 1

3 methods of local control via intercellular communication

- gap junctions (eg. cardiac muscle)

- contact-dependent (eg. immune)

-autocrine (molecules move a small distance through interstitial fluid

neurohormones

chemicals released by neurons into blood for action at distant targets

simple vs complex reflex

simple - either nervous or endocrine system

complex - both systems, several integrating systems

in reflex control, cells at a distant site control the response (vs. local change)

types of sensors

central receptors (eg. eyes, ears), peripheral receptors (eg. chemo and osmoreceptor), cell membrane/intracellular receptor proteins

neural vs endocrine reflex-specificity

neuron terminates in single target cell(s); most cells are exposed to hormone, response depends on if cell has receptor

neural vs endocrine reflex - nature of signal

neural has electrical signal through neuron, then chemical neurotransmitters; endocrine has chemical signals secreted in blood

neural vs endocrine reflex - speed

neural is faster

neural vs endocrine reflex - duration of action

neural is shorter

neural vs endocrine reflex - coding for stimulus intensity

neural signals are identical in strength, code with increased frequency; in endocrine, stimulus intensity relates to amount of secreted hormone

key features of hormones

can be made in different places, chemicals made by cells in specific endocrine glands, transported in blood to distant targets, bind specific receptors, may act on multiple tissues, action must be terminated

synthesis, release, transport in blood, examples of hydrophilic and hydrophobic hormones

hydrophilic- made in advance and stored, release by exocytosis, dissolved in blood, eg. peptide/protein hormones, catecholamines

hydrophobic - made on demand, released by diffusion, bound to carrier proteins in blood, eg. steroid and thyroid hormones

peptide hormones

3 or more AA, synthesized like secreted proteins, short half life in plasma, eg. insulin, hydrophilic so dissolved in plasma

post-translational processing of peptide hormone

preprohormone bound to signal sequence, signal gets cut off, peptide fragments on prohormone get off, produce active hormone

disulfide bonds on proinsulin

regions with disulfide bonds can get off, forming insulin, and the remaining C-peptide is a byproduct and can be used to indirectly measure insulin release

preprohormones

- can contain several copies of same hormone

- can contain more than one type of hormone

- active peptides released depends on specific proteolytic processing enzymes and cell type

steroid hormones

derived from cholesterol, longer half-life, eg. sex steroids like estrogen, cortisol, hydrophobic and bulky so bound to transport proteins in blood

type of steroid hormone made depends on which enzymes are present in the cell

eg. cholesterol can be made into aldosterone or cortisol in adrenal cortex or estradiol in ovary

monoamine hormones

derived from single AA (Trp or Tyr), eg. catecholamines like epinephrine, thyroxine, hydrophilic so dissolved in plasma

Trp vs Tyr derivatives

Trp: melatonin (behaves like peptides or steroids)

Tyr: catecholamines - dopamine, norepinephrine, and epinephrine (behave like peptides), thyroid hormones - thyroxine, T4, triiodothyronine, T3 (behave like steroids)

melatonin

darkness hormone, secreted at night, made in pineal glannd

synthesis of catecholamines (pathway from Tyr)

made in adrenal medulla, stored in vesicles and released via exocytosis, goes from Tyr - DOPA - dopamine - norepinephrine - epinephrine

how do stimuli trigger hormone release from endocrine cells

- change membrane potential

- increased [Ca2+] in cytosol

- change enzymatic activity

- increase transport of hormone substrates into cell

- alter transcription of genes coding for hormones or for enzymes needed for hormone synthesis

- promote survival, sometimes growth of endocrine cell

glucose stimulation of insulin release in pancreatic beta cell

glucose uptake by GLUt2 transporter, glucokinase phosphorylates, glycolysis leads to increased ATP, ATP blocks K+ efflux from ATP-sensitive potassium channel, depolarization, opening of voltage-gated calcium channel, stimulate movement of vesicles, release insulin (remember, it's a peptide hormone)

hypothalamus-pituitary axis

peripheral endocrine gland hormone (eg. cortisol from adrenal cortex) has negative feedback on anterior pituitary hormone and hypothalamic hormone; anterior pituitary hormone has negative feedback on hypothalamic hormone

anterior pituitary

releasing/inhibiting hormones from hypothalamus travel through portal vessels

anterior and posterior pituitary (not an endocrine gland!)

synergistic, permissive, antagonistic effects

synergistic - multiple hormones act together for greater effect (eg. FSH and testosterone increase sperm production), permissive - one hormone enhances target organ's response to a later hormone (eg. estrogen prepares uterus for action of progesterone), antagonistic - eg. insulin and glucagon

properties of receptors

large proteins, families, can be multiple receptors for one ligand or more than one ligand for a receptor, variable number in target cell, can be activated and inhibited, located in cell membrane, cytoplasm, nucleus, SATURABLE, high affinity for ligand, specific, reversible

slow and fast response to hormone binding to receptor

slow - synthesis of target proteins (if bound to cytosolic or nuclear receptors - directly alter gene transcription, hormone-receptor complex binds the hormone response element (HRE))

fast - modification of existing target proteins (binding to cell membrane receptor)

hormone response elements

specific DNA sequences; only genes with response elements will be activated/repressed

sometimes receptors recruit co-repressors to inhibit transcription

types of plasma membrane receptors

G protein-coupled receptors, receptor-enzyme, (receptor-channel, integrin receptor)

GPCR's

cytoplasmic tail linked to G protein, a 3-part transducer

signal transduction using adenylyl cyclase-cAMP system

some GCPRs some lipid second messengers like DAG and IP3

Gs protein - adenylyl cyclase

GTP added onto its alpha subunit, activates adenylyl cyclase (amplifier enzyme), converts ATP to produce cAMP, which activates protein kinase A, phosphorylating proteins and producing cellular response

Gq protein - phospholipase C

alpha subunit of Gq activates phospholipase C (PL-C, an amplifier enzyme), PL-C makes DAG (which remains in membrane) and IP3 (which diffuses into cytoplasm), DAG activates protein kinase C, while IP3 causes release of Ca2+ from organelles

Galpha i

inactivates adenylyl cyclase

fight or flight response by GPCRs (epinephrine)

glucose and fatty acid release, muscle contraction, vasodilation in skeletal muscle and blood vessels, vasoconstriction in intestine, skin, kidney

- epinephrine can bind to different isoforms of adrenergic receptor (alpha-receptor+epinephrine -> vasoconstriction; beta2-receptor+epinephrine -> vasodilation)

different adrenergic receptors of epinephrine and the G proteins they're coupled to

beta1 and beta2 - Gs, alpha2 - Gi, alpha1 - Gq

how is signaling modulated

hormone degraded, receptor down- or up-regulation, receptor desensitization, breakdown of second messengers, negative feedback, ENDOCYTOSIS/EXOCYTOSIS OF MEMBRANE RECEPTORS TO TURN THEM OFF (stimulated by ligand binding)

some functions of calcium for normal physiology

intracellular signaling, hormone secretion, blood clotting, neural excitability, muscle contraction, building/maintaining bone

where is calcium found?

bone (99%), ECF (0.1%), intracellular (0.9%)

osteoblasts, osteoclasts, osteocytes

osteoblasts - bone forming

osteoclasts - break down bone (fusion of many cells)

osteocytes (previously osteoblasts) - maintain bone

bone resorption

in osteoclasts, CO2 and H2O convert to H+ and HCO3- via carbonic anhydrase, provide low pH and proteases to release Ca2+ that enters bloodstream

RANK/RANKL interaction

osteoblasts promote osteoclast formation

- inactive osteoclast precursors have RANK receptor

- osteoblast has RANKL (RANK ligand)

- when RANKL binds RANK, osteoclast differentiates and fuses to form active osteoclast

OPG

secreted by osteoblasts, binds to RANKL to block RANKL/RANK interaction eg. Denosumab

PTH generally

- released from parathyroid glands

- increase plasma Ca2+

- stimulated by low plasma Ca2+

- peptide hormone

PTH effects on bone

acts on osteoblasts by increasing cAMP to increase RANKL and decrease OPG, more osteoclasts formed

PTH effects on kidney

increase Ca2+ reabsorption at distal tubule, increase calcitriol synthesis

Ca2+ sensing receptor to monitor extracellular Ca2+

- parathyroid cell

- calcium binds to GPCR

- inhibit PTH secretion, inhibit parathyroid cell growth, increase VDR expression which reduces PTH synthesis

formation of calcitriol (vit D3, 1,25-dihydroxycholecalciferol) - involves PTH!

skin converts 7-dehydrocholesterol to cholecalciferol (vit D3 NOT hormone)

liver converts cholecalciferol to 25-hydroxycholecalciferol

PTH in kidney converts 25-hydroxycholecalciferol to calcitriol (active)

calcitriol general

targets intestine, bone, kidney

increase plasma Ca2+, mainly by Ca2+ uptake from small intestine

- Ca2+ isn't easily absorbed, need calcitriol to help

calcitriol binds to VDR (vit D nuclear receptor)

- calcitriol is lipophilic

- binds to VDR and diffuses into nucleus

- binds to VDRE (vit D response element)

- activated transcription of mRNA that will be translated to Ca2+ channels

controlling blood phosphate

- bone is made of hydroxyapatite crystals

- PTH - loss of phosphate (increase phosphate release from bone, decrease phosphate reabsorption in kidney)

Calcitriol - retain phosphate (increase phosphate absorption by intestine and reabsorption in kidney)

calcitonin general

- secreted by C cells (AKA parafollicular cells) in thyroid

- peptide hormone

- triggered by high plasma Ca2+

- acts to decrease (tone down) Ca2+

- C cells also have Ca2+ sensing receptors (like parathyroid cells)

how does calcitonin decrease plasma Ca2+

(by decreasing plasma Ca2+, you're retaining more Ca2+ in bone, protecting skeleton from Ca2+ loss during pregnancy and lactation)

- reduce activity of osteoclasts

- stimulates osteoblasts to deposit calcium

- inhibit calcium reabsorption in kidney

hyper and hypocalcemia

hyper - constipation, fatigue, depression, bone pain, kidney stones

hypo - arrhythmias, spasms, seizures

water distribution in body

2/3 in ICF, 1/3 in ECF (75% interstitial fluid, 25% plasma)

body is roughly 55% water

effects of too much or too little water

too little - less ECF, decreased BP, make no urine

too much - backs up in lungs, legs, abdomen, difficulties in breahting/walking

urine formation in the nephron

filtration - reabsorption + secretion = excretion

collecting duct is regulated by hormones

vasopressin (AKA ADH) general

- increase water reabsorption

- increase blood volume and BP

- made in hypothalamus, secreted from posterior pituitary

- peptide hormone

regulation of vasopressin release

stimulated by high plasma osmolarity (detected by osmoreceptors in hypothalamus)

also by low BP (detected by reduced stretch of walls of atria and baroreceptors)

how does vasopressin increase water permeability

inserts aquaporin water pores on apical membrane (facing lumen) in collecting duct cells via signaling cascade initiated by cAMP

aldosterone general

- steroid hormone

- made in adrenal cortex

- increase sodium (and water) reabsorption and potassium secretion

- acts on distal tubule and collecting duct

control of aldosterone synthesis (negative feedback)

- high plasma K+ stimulates aldosterone synthesis

- decreased BP stimulates aldosterone synthesis (angiotensin II, RAAS pathway)

- high osmolarity in ECF inhibits aldosterone synthesis

aldosterone intracellular mechanism on distal tubule and collecting duct cells

diffuse into cell, initiate transcription in nucleus, make new sodium and potassium channels and sodium-potassium ATPase, prevent degradation of apical Na channel

RAAS pathway

- renin secreted by juxtaglomerular cells (well-positioned to sense BP) when BP falls

- liver makes angiotensinogen, renin converts angiotensinogen to angiotensin I

- ACE in lungs converts angiotensin I to angiotensin II

- angiotensin II increases vasopressin, stimulates thirst, vasoconstricts, increases proximal tubule Na retention

Natriuretic peptides

- ANP, BNP, CNP all secreted by secondary endocrine glands

ANP

released by atrial myocardial cells (senses increased BV and atrial stretch) (and neurons)

- decrease Na and H2O reabsorption

- increase K reabsorption

- suppress renin, aldosterone, vasopressin

- increase NaCl and H2O excretion (increased GFR)

- decreased sympathetic output

- decreased blood volume and BP

what does the blood-brain barrier divide?

blood and interstitial fluid, blood and CSF (no barrier between interstitial fluid and CSF)

dopamine injection, MSG and BBB

dopamine can't cross BBB, need to inject L-dopa which can cross

MSG can't cross BBB, but activates glutamate receptors on outside, increased thirst, stiff neck

where is the BBB broken

- neurons need to communicate freely with bloodstream eg. hypothalamus and pituitary to release hormones

- circumventricular organs around 3rd ventricle - neurons sense specific chemical []

3 types meninges

dura mater - very tough membrane

arachnoid membrane - delicate tissue

pia mater - lies on top of brain, tethered to arachnoid by "trabeculae"

subarachnoid space

between arachnoid membrane and pia mater

brain floats to protect from mechanical stress

have blood vessels (capillaries to brain tissue)

BBB exists between capillaries and brain tissue

reticular formation

- collection of loos nerve cells connecting brain to behaviour

- sits b/w brain and spinal cord

- teethguards protect reticular formation, prevent going unconscious

what constitutes the BBB

usually endothelial lining of BV mostly has fenestrations, but in brain endothelial cells lining capillaries have no gaps (everything must be transported)

types of ventricles and canals

lateral - paired, large curving structure across midline

third - right in middle, under cerebral hemisphere

3rd and 4th communicate via "Aqueduct of sylvius"

from 4th ventricle, central canal

*continuous connection b/w ventricles

flow of CSF

CSF made in choroid plexus, drains through central canal, moves to outer parts of brain (subarachnoid space), exits at top of brain into large venous sinus

*circulation occurs w/o pump

where is CSF produced

- most is produced by choroid plexus lining ventricles (some produced in brain capillaries)

- made of epithelial cells connected by tight junctions

- continuously produces CSFF to circulate cleansing mechanism

- dense network of capillaries ballooning out into ventricular wall so everything must be transported

arachnoid villi

- about 1/2 CSF drains through these into venous system

- out pouching of arachnoid tissue, sticks out through dura matter into venous sinus

composition of CSF, where is it mostly found

- same osmolarity and [Na] as blood

- reduced K, Ca, Mg (similar to interstitial fluid)

- total vol-215mL (cranial 140 - 25ml ventricles, 115 subarachnoid; spinal - 75)

- most CSF is in subarachnoid space

- we make 550 ml per day, so cycle 3x

lumbar puncture (spinal tap)

collect sample of CSF for analysis

astrocytes (glycolysis)

- provide bridge between neurons and blood vessels with "end feet"

- efficient at glycolysis

- absorbs glucose from capillary, producing lactate as end-product, lactate is substrate for ATP production

- remove neurotransmitters (since near synapse)

- will line up single file since following blood vessels

- regulate local blood flow

regulation of local blood flow by astrocytes

glutamate in synapses triggers Ca release within astrocytes, Ca wave travels through astrocyte and triggers PGE2 (prostaglandin) release at end-foot

PGE2 causes vasodilation and increased blood flow

facilitated diffusion

- carrier protein aids movement of polar molecules (selective)

- down [] gradient

- number of transporters will eventually saturate

secondary active transport

molecule transported against [] gradient, without ATP

voltage sensing mechanism of voltage gated channels

S4 segment, positively charged, normally attracted downwards towards negative inner membrane

(when membrane depolarizes, no longer attracted, and wing lifts up, opening the pore)

2 types exocytosis

kiss and run- vesicle connects/disconnects several times before contents are emptied, low rate of signaling

full - total release of vesicle contents at once, high rate of signaling **must be counterbalanced by endocytosis to stabilize membrane surface area

what potential difference does Na-K pump contribute

-10 mV (Na/K inequality - 3 Na out, 2 K in), since resting MP is -70 mV this is due to K efflux via K channels

nernst equation

potential difference across membrane, inside wrt to outside, at equilibrium

*only valid for one ion species diffusing

equilibrium potential of K

-90 mV (actually -70 bc movement of other ions eg. slight influx of Na)

equilibrium potential of Na

+60 mV

Cl- concentration inside/outside cell

large proteins inside cell with negative, so negative Cl gets repelled and more Cl outside than inside

how to open activation gate (S4 segment) of voltage gated sodium channels

depolarize membrane (stays open as long as it's depolarized)

inactivation gate of voltage gated sodium channels

inactivation gate closes after rapid depolarization and half ms after activation gate opens

*if there was no inactivation gate, MP would go towards equ'm potential of Na (60 mV)

how to remove inactivation of Na channel

MP needs to fall below threshold

types of stimuli

subthreshold, threshold, suprathreshold

refractory period - 2 types

after AP generated and inactivate Na channels, there's a period where all or some Na channels are inactivated

(remain inactivated until MP drops below threshold)

- absolute-none of channels reconfigured (can't generate AP at all)

- relative-some, but not all channels reconfigured

depolarization block (how to create)

permanently depolarize membrane so another AP can't be generated

- destroy K+ gradient, by injecting K+ into ECF so K+ no longer leaves cell

after-hyperpolarization

extra voltage-gated K+ channels (and K leak channels) so greater outward K+ current, causing MP to be more polarized than normal

*voltage-gated K+ channels open when membrane is depolarized, much like voltage-gated Na channels

excitable cells

- most cells aren't excitable, lack voltage-gated Na channels

- can conduct passive currents but can't generate APs

- only neurons with long axons and muscle cells generate propagating APs

cable properties - length constant lamda

how far you can carry potential difference before it drops to 37% of original value

- defined with internal resistance, extracellular fluid resistance, membrane resistance (extracellular fluid resistance doesn't change)

- proportional to sqrt(Rm/Ri)

how to increase lambda

- increase lamda by increasing diameter (less internal resistance) (drinking out of multiple straws)

- increase lamda by increasing membrane resistance (less current leaks out) (taping shut holes in a straw)