final Flashcards
3 types of muscle
- development of skeletal muscle
- Skeletal muscle – makes up muscular system
a. Includes diaphragm
b. Multinucleated – more than one nucleus per cell
- During development – many muscle cells fuse; contain multiple nuclei as a result
c. Striated – due to proteins/filaments
d. Long, stacked in parallel
- each individual muscle cell/fibre is long and skinny
- many are stacked together – go from one end to the other end of the muscle - Cardiac muscle – found only in the heart
a. Uninucleated
b. Striated – dark and light bands
c. Don’t only lay parallel – also stacked end to end
- joined via intercalated disk – region where one cardiac muscle cell contacts other at end - Smooth muscle – appears throughout the body systems as components of hollow organs and tubes
a. Key component of blood vessels – allows them to contract
b. Uninucleated
c. Not striated
d. Sheets or tubes – often spindle shaped; not as long as skeletal muscle cells
Muscle contraction allows
Classifications
Muscle contraction allows
- Locomotion – movement of joints, limbs and whole body
- Propulsion of contents through various hollow internal organs – movement of blood through the circulatory system; food through digestive system
- Emptying of contents of certain organs to external environment – sphincters act as valves; allows defecation and urination
Classified as either
- Striated or unstriated (better)
- Voluntary or involuntary
2 neuron chain of NMJ
Upper Motor Neurons – cell body in the motor cortex; synapse on LMN in the spinal cord
• Approx. 90% desiccate in the medulla – primary neurons on right side control left body
Lower Motor neurons – cell body in ventral root spinal cord; axons synapse on muscle cells
a. Activation of lower motor neuron causes contraction of muscle cells
• Neuromuscular junction
b. Motor unit – the group of muscle cells controlled by one LMN
i. Mammals – each muscle cell receives only one synapse
• Always excitatory – Ach
• LMN – can innervate one (more rare) or many muscle cells (more common)
ii. Other vertebrates – can have 2 synapses
NMJ differences
- summation
Very large
• NMJ – 1000 μm2
• Central synapse – 0.05 μm2
Highly folded – increases surface area
a. Crests – high density of nicotinic AChR (hundreds of thousands)
• High density causes large EPSP
b. Troughs – lots of voltage gated Na+ channels
Causes large EPSP – approx. 30-50mV (central synapse is approx. 0.5-1mV)
• always enough to stimulate opening of Na+ channels & fire AP
A single AP of LMN is always enough to cause AP in muscle cell
• No summation of EPSP – excitation will always result in contraction
• High safety factor
Structure of muscle
Consists a number of muscle fibers (cells) lying parallel to one another and held together by connective tissue
- Tendon – end of muscle; tough CT
- Muscle fascicle – bundle of cells/fibres within muscle; surrounded by CT
- Single skeletal muscle cell is known as a muscle fiber
a. Large, elongated, and cylindrically shaped
b. Fibers usually extend entire length of muscle
Structure of muscle cells
a. Multinucleated
b. Myofibrils – bundles of contractile proteins within cell
c. Sarcoplasmic reticulum – specialized endoplasmic reticulum; surrounds myofibril
• Always sits with middle in the middle of the sarcomere (middle of H zone)
• Stores Ca2+ ions
d. Sarcolemma – membrane of muscle cell
e. T-tubules – form a mesh of canals through muscles
• Have openings through sarcolemma
• Lie adjacent to & sits between sections of SR
Structure of myofibril
- proteins of M line!
- Sarcomere – z line to z line
• M line – middle of H zone
• Only thick filaments at rest
• A band – length of thick filaments - Thick filaments
a. Mainly myosin – protein molecule; 2 identical subunits shaped like golf club
i. Tail ends – intertwined around each other
• Oriented towards center of filament
ii. Myosin heads – globular ends project out from hinge at regular intervals
• Form cross bridges between thick and thin filaments
iii. 2 binding sites – critical to contraction
• Actin binding site
• Myosin ATPase
iv. A motor protein – hydrolyses ATP to convert chemical energy to carry out mechanical work - Thin filaments
a. Actin – primary structural component of thin filaments
• G-actin monomers are spherical – assemble into long chains
• Each actin molecule has a special binding site for attachment with myosin head
b. Tropomyosin – threadlike molecules; interact with actin along its spinal grove
• Covers myosin binding site
c. Troponin
i. 3 polypeptide units
• One binds to tropomyosin
• One binds actin
• One binds with Ca2+
ii. Unbound – troponin stabilizes tropomyosin ni blocking position
iii. Bound – tropomyosin uncovers binding site; allows formation of cross bridges & contraction
d. Nebulin – runs along the middle of actin ball chains & aligns actin filaments - Titin – giant elastic protein
a. Joins M-lines to Z lines at opposite ends of sarcomere – the whole length of sarcomere
b. Two important roles:
• Helps stabilize position of thick filaments in relation to thin filaments – keeps the thick filaments in the middle of thin filaments
• Improves muscle’s elasticity – sarcomere can get longer and shorter - Myomesin – main protein of M line
• Structural element – keeps thick filaments at regular intervals
Excitation Contration coupling
- sliding filament hypothesis
- process
- what bands are t-tubule and SR on
- do actin and myosin contract
- what happens to Ach
- calsequesterin!!
Sliding filament hypothesis – muscle shortens when actin and myosin slide past each other
Process
1. AP from LMN – causes release of Ach into synaptic cleft of NMJ
- ACh binds to the receptor – nicotinic AChR
a. Allows entry of Na+ through voltage gated channels
b. Causes EPSP large enough to trigger an AP – AP travels across membrane of cell - AP invades the T-tubule system – continuous with sarcoplasm
a. T-tubule – run perpendicular from surface of muscle cell into central portions of fibres
i. Aligned on edges of A band – directly adjacent to thick myofilaments/myosin
b. Causes voltage gated dihydropyridine (DHP) receptors to open – channel within t-tubule; blocked by dihydropyridine drug
i. Allows for small amount of Ca2+ to enter into cell
c. DHP is connected to RyR channel via RyR foot – piece of globular protein
i. Ryanodine receptor – channel within SR; blocked by ryanodine drug
- Physically pulled open
- Opening causes a massive release of Ca2+, and increase in intercellular Ca2+ concentration - Ca2+ binds troponin
a. At rest – myosin head is cocked in the absence of Ca2+
i. Tropomyosin is blocking the binding of myosin to actin – only weakly bound to actin
b. Binding of Ca2+ to troponin molecules – pulls tropomyosin away from binding sites on actin
i. Allows myosin to bind to actin
ii. Power stroke – cross bridges bend
- Myosin heads move thin filaments towards M line – releases Pi
- End of power stroke – releases ADP; tightly bound in rigor state
iii. Cross bridges release when ATP binds
- Hydrolyzation of ATP to ADP + Pi – energy allows cocking of myosin head
- Weakly bound to myosin at this stage
- Can binds to more distal actin site as long as Ca2+ is available to bind tropomyosin
- Repeating cycle shortens sarcomere – actin filaments slide closer to M line
c. Causes contraction of sarcomere – actin and myosin DO NOT contract - When AP stops arriving at NMJ
a. Ach dissociates from receptor & is degraded by AChE
i. Choline is recycled back into synaptic terminal
b. Free Ca2+ pumped back into SR from cytosol via ATPase – powerful ATPase transporter
i. Calsequestrin protein – binds Ca2+ and helps sequester
ii. Ca2+ dissociates from troponin – pumped into SR
c. Tropomyosin moves back in front of binding sites
i. Muscle is unable to maintain tension
d. Actin and myosin slip past each other
i. Pulled apart by titin & antagonistic muscle (ex. triceps contracting will cause stretching of bicep sarcomeres)
Rigor Mortis
Rigor state – myosin head is tightly bound to actin site; release via binding of ATP to myosin
a. ATP -> ADP + Pi causes reactivation of myosin head into cocked position – ready to bind again
- Will continue to bind as long as Ca2+ is available and will continue to shorten the muscle
~3-4 hours after death, peak at ~12 hours – muscle becomes very stiff
a. SR becomes leaky – intracellular Ca++ rises
b. Ca++ allows troponin-tropomyosin complex to move aside and allow myosin cross bridges to bind to actin.
• Release of ADP and Pi results in rigor state binding
c. Dead cells do not produce ATP – cross bridges cannot detach
Rigor mortis subsides when enzymes start to break down myosin heads
– Muscle is starting to break down
Energy use in muscles
- Splitting of ATP by myosin ATPase for power stroke
- Active transport of Ca2+ back into sarcoplasmic reticulum
a. Ca2+ ATPase pumps - Na+/K+ ATPase
a. Neurons and muscle cells need to maintain RMP in order to generate AP
Main energy sources for muscle contraction
- bloodflow requirements
- enzyme requirements
- what type of exercise
- Stored ATP (very little stored) – only have enough stored for a few seconds worth of activity; up to a minute
- Creatine phosphate – first energy storehouse tapped at onset of contractile activity
a. Creatine kinase – enzyme catabolizes bidirectional transfer between ATP and creatine
b. At rest – ATP demand is low
i. Creatine kinase transfers Pi from ATP to creatine
- Creatine phosphate = phosphorylated creatine
ii. Allows storage of energy as creatine phosphate
c. When energy is needed
i. Creatine kinase phosphorylates ADP from Pi on creatine
- ATP is used for contraction
- Provides 4-5 times the energy of stored ATP
- Limited supply (only a few minutes)
Most energy for long term sustained contraction comes from oxidative phosphorylation and anaerobic glycolysis
- Oxidative phosphorylation – takes place within muscle mitochondria if sufficient O2 is present
a. Provides energy during light to moderate exercise
b. Uses stores of glycogen in muscle (30 min) – depolymerizes to glucose
i. Good yield of ATP – 38 per glucose molecule
c. Aerobic exercise – requires adequate supply of oxygen
i. Increased blood flow via
- Increase ventilation
- Increase heart rate and force of contraction
- Dilate skeletal blood vessels - Anaerobic Glycolysis – primary source of ATP when o2 is low
a. Supports anaerobic & high-intensity exercise – oxygen supply is limited
b. Rapid supply of ATP
- Only a few enzymes involved – fewer enzymes than in oxidative phosphorylation
c. Very low ATP yield – only 2 ATP per glucose molecule
- Lactic acid – acidifies muscle and contributes to fatigue
- Duration of anaerobic glycolysis is limited
Causes of muscle fatigue
Central fatigue
a. Psychological
• “I just can’t” – differs person to person
• Plays larger role for elite athletes
Peripheral – plays larger role in majority of population; physiologists are unsure which is most important
a. Decrease in release of ACh from LMN with sustained activity
b. Receptor desensitization – when receptors are repeatedly exposed, they can lower affinity for ligand
c. Changes in of muscle RMP
• If muscle is very active – firing a lot of AP
• Eventually – you will see slight changes in ECF K+
• Causes depolarization of cells – can lead to inefficiency
d. Impaired Ca2+ release by SR – RyR may not be as effective at allowing Ca2+ into cell
e. Intracellular pH of muscle – due to lactic acid from anaerobic activity
f. Others….
Generation of tension
- timing of AP in neuron vs muscle cell
Electrode in motor neuron & in muscle cell – allows us to see timing of events
AP arrives from LMN
a. AP in muscle cell approx. 2 ms after neuronal AP
Tension generated in muscle – experiences lag
a. Latent period – due to:
• AP propagating in muscle
• Opening of DHR and RyR receptors – flooding of Ca2+
• Interaction of Ca2+ with myosin heads – pulling of tropomyosin away
b. Contraction phase
c. Relaxation phase
Types of stimulation
- Simulation at low frequency – muscle cell generates tension and relaxes
- Stimulation at higher frequency – stimulating muscle cell before it’s relaxes
a. Analogous to GP summation – can generate tension before single twitch has been allowed to relax - Summation leading to unfused tetanus
a. Stimulating repeatedly before relaxation – stimulated to maximum tension
b. Max tension – point of tetanus
- Unfused – still getting to relax slightly from one pulse to the next - Summation leading to complete tetanus – stimulated too quickly to get opportunities to start to relax
a. This is the most amount of tension that a muscle cell can generate
- Maximum tension is usually higher than unfused tetanus
Maximum tension
- 2 theories
requires several AP to occur; 2 theories (both likely contribute)
- Some think it takes several APs to increase intracellular Ca++ enough to saturate actin’s myosin binding sites
a. The concentration of Ca2+ doesn’t get high enough with single AP - Some think intracellular Ca++ reaches its maximum (saturates) after first action potential.
a. Summation and Tetanus develop because sustained elevation of increased Ca++ allows greater exposure of actin binding sites and therefore maximizes interaction with myosin (effect is time dependent)
b. More time dependent than concentration dependent
Length tension
the amount of tension a muscle can generate depends on initial resting state
Optimal resting length – we can generate the most tension from fibre when thin filaments only overall until the end of the myosin heads (medium amount of overlap)
Stretching – less overlap; muscle cell can’t generate as much tension because there’s not as many myosin heads able to interact with actin
Compressed – pushing thin filaments towards m line; can’t generate as much tension because contracted sarcomere has many proteins within cell
o All the other molecules start to push against each other – work against the generation of tension
Types of skeletal muscle fibres
- chickens vs mammels
- 3 types & features!
- In chickens and turkey – fibres are grouped together
o White meat – white muscle
o Dark meat – red muscle - Mammals – fibres are interspersed
o Different fibre types may coexist side by side
3 types of motor fibres/units – all muscle fibres within the same unit are the same type
- Slow twitch oxidative – slow & fatigue resistant
a. Small amounts of tension, slowly
i. Capable generating tension for long periods of time without running down energy stores
- Single twitch – approx. 2 grams tension
- Approx. 25 ms to generate full tension
- Unfused tetanic force – generates max force after approx. 1 second
ii. Tension can be sustained over long period of time – stays consistent up to an hour
b. Features
i. Large numbers of mitochondria
ii. Small fibres
iii. Well vascularized – myoglobin to facilitate oxygen transfer from blood
- Blood – makes them red; supplies with o2 - Fast oxidative-glycolytic – fast & fatigue resistant
a. Can do both oxidative and glycolytic – o2 or no o2
i. Generate a lot of tension, moderately fast
- Single twitch – approx. 10 grams tension
- Unfused tetanic – takes a few stimulations to reach peak
ii. Somewhat resistant to fatigue – can maintain tension with gradual decrease approx. 15 min
b. Features
i. Moderate # of mitochondria – fewer than slow twitch
ii. Fibres are larger than slow twitch - Fast twitch glycolytic – fast fatigable & only anaerobic
a. White muscle – no o2; does not require o2 to be transported here
i. Generate the most tension
- Single twitch – approx. 50 grams
- Approx. 10 ms to generate full tension
- Unfused tetanic – very few stimulations required to reach peak; faster than others
ii. Fatigue rapidly – can only generate max tension approx. 1 min
b. Features
i. Few mitochondria – breakdown glucose via anaerobic catabolism
ii. Fibres are larger than slow twitch – these are the largest & most tension
Recruitment of motor units
- size of motor units
Slow twitch fatigue resistant – first Motor units recruited; red & oxidative
a. Ex. these will be activated if lifting a light weight
b. Smallest motor neurons
- Each MU has only a few fibres
Fast fatigue resistant – second recruited
a. Motor neurons are slightly larger
Fast twitch glycolytic (fatigable; white muscle) – last recruited
a. Ex. lifting a very heavy weight
b. Largest motor units – most fibres
- Motor unit has many fibres
Size principle – size matters
Homeostatic control mechanisms
Organs that have endocrine functions
Set point range (examples) & integration
Homeostatic control mechanisms – allows coordination between body systems
Many not classically endocrine organs have endocrine functions
Maintain set point range – metabolism, salt and water, reproduction, growth
Requires integration
• Positive input – stimulation
• Negative input – inhibition
Origins of endocrinology
Early 20th century – William Bayliss and Ernest Starling
Identifying cause and effect functions
• Anatomy (form) and physio (function)
Hypothesized control of secretion of alkaline juice from the pancreas into the duodenum – nervous of chemical control?
a. Began with Pavlov’s dog experiment – is there endocrinology associated with it
b. Anatomically
o Stomach goes into duodenum & pancreas opens into duodenum
c. Physio
o The stomach produces acidic chyme – too acidic for duodenum to digest properly
o Pancreas secretes alkaline juices
Experiment
a. Severed neurons that connected pancreas in dogs – found there was still entry of alkaline fluids into duodenum
b. Concluded a blood borne agent
o Stimulus of endocrine agents – promotes pancreas to release endocrine juices & alkaline juices
c. Secretin – later was identified as the hormone that promotes secretion of alkaline fluid from pancreas
Presented these findings in 1905 in the royal college of physicians of London
a. Pharmacopoeias – a legally binding collection of standards and quality specifications for medicines used in a country or region
b. Hormone – Greek for “I excite or arouse”; carried from the organ where they are produced to the organ which they affect by means of the blood stream and the continually recurring physiological needs of the organism must determine their repeated production and orientation through the body
- Released from an endocrine gland into circulation and acts at far site
- This is not entirely true – there are many types of hormones
Variability in hormone effects and production (7)
- tropic vs nontropic
- rhythms
- One endocrine gland can produce many hormones
a. Ex. pituitary gland - The same hormone can be secreted by many tissue types
a. Every cell in the body has the mechanisms to transcribe genes and produce hormones
i. Ex. the brain – not a traditional endocrine gland but has endocrine functions
b. Estrogens and androgens are often sex specific (secreted by sex organs)
i. Also released in other areas – ex. release of estrogen in the brain for neuromodulation - There is more than one target cell for a single hormone
a. Ex. a hormone released to control blood pressure may affect:
i. Endothelial cells of blood vessels
ii. Kidney – controls blood volume
b. Integrates function of different organs - A target cell can be influenced by many hormones
a. Non-tropic hormones – hormones that directly stimulate target cells to induce effects
b. Tropic hormones – act on another endocrine gland to initiate release of other hormones - Secretion varies over time and will be affected by changes in the environment
a. Rhythms – release of hormones is entrained to environmental cycles which vary in interval length and duration
i. Growth hormones – peaks at night
ii. Cortisol – usually peaks in the morning
iii. Melatonin – peaks as night - Hormones can be blood borne or neuronally derived
a. Found in the brain – can regulate neuron function - Hormones can be excreted from tissues that have other functions
Chemical classifications of hormones
- solubility
- type of secretion
- transport
- location
- Peptides – chains of amino acids (3 to 500+)
a. Solubility – hydrophilic
b. Secretion – exocytosis
c. Transport – free active peptide or precursor (inactive form that may be activated via post translational modification)
d. Source – pituitary, pancreas, GI tract etc
i. Occurs everywhere – every cell has mechanisms to secrete proteins - Amino acid derivatives
a. Catecholamines (ex. norepinephrine and epinephrine)
i. Solubility – hydrophilic
ii. Secretion – exocytosis
iii. Transport – 50% to carrier protein
iv. Main source – adrenal medulla
- Not the only site
b. Thyroid hormone (T3 and T4)
i. Solubility – hydrophobic
ii. Secretion – endo & exocytosis
iii. Transport – most bound to carrier
- Hydrophobic relies more heavily on carrier proteins
iv. Source – thyroid gland
- The most specific in terms of cite of synthesis – chemical conditions to synthesize are very harsh
c. Melatonin
i. Solubility – hydrophilic
ii. Secretion – exocytosis
iii. Transport – 50% to carrier protein
iv. Source – pineal gland - Steroids – cholesterol derivatives
a. Solubility – hydrophobic
b. Secretion – diffusion (non polar and small)
c. Transport – most bound to carrier protein
i. Hydrophobic relies more heavily on carrier proteins
d. Source – adrenal cortex and sex steroids
i. Adrenal cortex – cortisol and aldosterone
Synthesis and most translational modification of peptide hormones
examples
- thyrotropin releasing hormone
- adrenocorticotrophic hormone
- Hormone is synthesized via transcription and translation
- Modifications in golgi – may be required in order to become bioactive
a. Undergoes peptide cleavage
b. Addition of functional groups
i. Glycosylation – addition of sugar
ii. Phosphorylation – addition of phosphate group
iii. Sulfation – addition of sulfide group
iv. Amidation – addition of amide group
v. Acetylation – addition of acetyl group
c. Subunit aggregation (ex. insulin receptors)
Examples:
Thyrotropin releasing hormone
- PreproTRH – precursor peptide has 6 copies of 3 AA TRH hormone
a. Must undergo proteolytic activation in order to release the TRH hormone
b. Protein segments in between may be protective – play a role in regulation but understanding of their role is limited - Adrenocorticotrophic hormone – produced in the pituitary
a. Pro-opiomelanocortin – prohormone for ACTH
i. May contain several peptide sequences with biological activity
ii. ACTH – regulates cortisol synthesis and release
secretion of hormones
- negative and positive feedback (and examples)
Feedback control is mainly negative – output counteracts input
a. Common in tropic hormones
- ex. release of TSH (thyroid stimulating hormone) from anterior pituitary -> promotes thyroid hormone synthesis -> releases TH (thyroid hormone) -> TH inhibits production of thyrotropin releasing hormone (TRH) in hypothalamus -> inhibits production of TSH in the pit gland
Can be positive
a. Ovarian cycles
i. Increasing maturation of follicles during ovulation causes increase in estrogen -> estrogen stimulates hypothalamus and causes release of gonadotrophin releasing hormone (GnRH) -> causes further increase in estrogen
b. Letdown reflex in nursing mothers
c. Oxytocin release in contraction of endometrium during birth/patriation
Carrier proteins
- where do hydrophobic vs phillic hormones illicit responses
- dictated by what
Release requires changes in environment – stimulus triggers synthesis and release of hormone
Free hormones bind to proteins and form complexes – very few free hormones within the blood stream
Carrier proteins
1. Often required for both hydrophobic and hydrophilic hormones
a. Hydrophobic – more reliant; more protein complexes than free hormones
o Genomic response – crosses membrane and binds to cytoplasmic or nuclear receptors; leads to transcription of new proteins
- Slow acting – seconds to minutes
b. Hydrophilic – may be bound more loosely
o Highly water soluble – more free hormones than bound
o Nongenomic response – binds to membrane receptors
- Fast acting – minutes to hours
2. Dictated by binding affinity – affinity of hormone to carrier will affect total amount of free hormone in circulation
Types of carriers – can be general or specific to hormone
1. Specific carriers
• Corticosteroid binding globulin (CBG) – carry corticosteroids
• Thyroid hormone binding globulin, thyroid binding globulin, & transthyretin – carry thyroid hormones
2. General carrier
• Albumin – many hydrophilic hormones bind; typically low affinity
Activation and inactivation of hormones
- half lives
- ex. of deg enz
Activation – metabolism of the precursor or release from carrier protein activation
1. Prohormone – inactive form of hormone often present in the blood
a. Common with peptide hormones – must undergo proteolytic activation
2. Released hormone has a half life in the blood – effects efficacy
a. Affinity to carriers will be influenced by energy required to synthesize hormones
• Steroids require lots of energy – will bind more tightly to carriers to prevent release and degradation in the blood
• AA derived – require less energy & won’t bind to carriers as tightly
b. General half lives
• Singe AA derivatives – 1 minute
• Peptide hormones – minutes to hours
• Steroid hormones – hours
3. Free hormones bind to receptors of cells – either membrane bound or within cytosol or nucleus response
a. Response generally resets balance in response to change – often negative feedback
Inactivation
1. Enzymatic degradation
a. Endopeptidases – enzyme that degrades peptide bonds in the interior of an AA chain
• Ex. trypsin – general endopeptidase
b. Exopeptidases – enzymes that release single AA from peptides chains by removing from the ends
2. Hormone receptor complex endocytosis – complex is taken into cell and inactivated
3. Conjugation – chemical group is attached
a. Sulfation – common for steroids
• Improves water solubility – will be present in solution, filtered by the kidney, and excreted
4. Inactive proteins can be excreted when no longer required by the body
Reflex pathways
- Neuroendocrine responses – combine neuronal and hormonal processes
a. Activation of neuron causes release of neurotransmitters from axon terminal -> acts directly on target cells (does not enter bloodstream) -> endocrine response
i. Ex. knee jerk response
ii. Uses neurotransmitters – still a neuroendocrine response
b. Activation of neuron causes release of neurohormones from axon terminal -> enters into bloodstream -> acts on target cells -> endocrine response - Hormone release with stimulation from neuron
a. Neurotransmitter is released from axon terminal onto endocrine gland -> causes release of hormone -> enters bloodstream - Complex neuroendocrine
a. Neurohormone released from axon terminal -> travels through bloodstream and stimulates endocrine gland -> causes release of hormone
Neuromodulation
nt in systems
effects
Not the same as neuroendocrine
Estrogen functions in neuromodulation
- Diffuse modulatory systems – neurons diffused throughout the brain that regulate many physiological functions and behaviour
a. Norepinephrine, Ach, serotonin, dopamine - Estrogens – reset the balance and receptivity of diffuse modulation systems
a. Can govern mood, appetite, and are involved in mood disorders (ex. depression and bipolar and anxiety)
Endocrine dysfunction
- levels of dysfunction (example)
- types of dysfunction
Levels of dysfunction
o Primary dysfunction – site of lesion for the active non tropic hormone (ex. adrenal gland, thyroid gland)
o Secondary dysfunction – dysfunction elsewhere in endocrine pathway
o Tertiary dysfunction – dysfunction at site of action of the hormone (ex. end organ resistance)
Ex. exogenous cortisol
a. CRH is released from hypothalamus -> stimulates ACTH release from ant pit -> stimulates release of cortisol from adrenal cortex
b. Primary dysfunction – occurs at adrenal cortex in release of cortisol
• This is the hormone that actually causes the response
Types of dysfunction
- Hyposecretion – can be primary or secondary; too little hormones or response
a. Usually the result of atrophy of the endocrine gland
i. Normally treated through replacement therapy – supply of substance lacking in body
b. Target cells may lack receptors or biochemical machinery at the target cell
i. Ex. hyperinsulinemia – type II diabetes
- There lots of insulin but response is malfunctioning - Hypersecretion – primary or secondary; too much hormone or response
a. Usually the result of a benign tumor (adenoma)
i. Normally treated through inhibition (antagonists)
b. Target cell responsiveness is altered naturally (decreased response due to decreased hormones present)
Effects of hormones at target cell
- 4 types
- binding kinetics
- law of mass action
- Up and down regulation – receptors at the target cell are regulated in response to hormone levels which influence abundance and affinity of hormone
a. Binding kinetics – how fast a compound binds to target and dissociates from it
i. Types and effects
- Competitive and allosteric
- Agonistic and antagonistic
ii. Reliant on abundance and affinity
b. Law of mass action (pg 47-48) – determines concentration of [hormone] and [receptor] vs [hormone receptor complexes]
- Equilibrium – association constant (Ka) drives the reaction both ways depending on the concentration of each
- At equilibrium: [hormone] x [receptors] x Ka = [hormone receptor complex] x Kd
i. Ka = association constant
- High Ka = high binding affinity or high [hormone]
ii. Kd = dissociation constant
- High Kd = low binding affinity or low [hormone]
c. Not all hormones complexes follow the law of mass action
i. Non cooperative law of mass action is upheld
ii. Positively cooperative ligand binding increases receptor affinity of vacant receptors
iii. Negatively cooperative ligand binding decreases receptor affinity of vacant receptors
- Permissiveness – hormone cannot have full effect without another hormone being present
a. Ex. T3 - Synergism – the combined effect of multiple hormones is greater than the sum of the parts
a. Ex. blood glucose levels are increased by the presence of cortisol and epinephrine - Antagonism – one hormone reduces the effectiveness of another hormone; can be direct or indirect
a. Pharmaceutical applications – drugs able to bind to receptors to inhibit the actions of an endogenous hormone/signaling molecule
b. Also occurs naturally
Types of hormone receptors
- what hydrophobic hormones
- Membrane bound
a. ligand gated; enzyme linked; guanylyl cyclase and GPCR
i. most common is GPCR
- 7 trans membrane domains (7 MSR)
ii. enzyme linked
- normally 1 MSR (single pass)
- ex. insulin receptors
iii. important in the NS and other excitable cells
b. Second messenger systems
i. Adenylate cyclase
- Linked GPCR
ii. Guanylate cyclase
- Linked to guanylyl cyclase receptors (1 MSR)
iii. Inositol phosphate and diacyl glycerol
- Linked to GPCR - Nuclear receptors – most lipophilic hormones act through; often a genomic response
a. Steroid hormone
i. Bind in cytoplasm or nucleus – will form a ligand transcription factor
- Affects transcription of genes and mRNA -> proteins
ii. Initially thought that all steroid acted through nuclear receptors
- More rapid response discovery in recent years indicates membrane bound receptors activation
- There are membrane bound receptors for progesterone, estrogen, thyroid hormones (all lipophilic)
The pituitary gland and hypothalamus
- structures
- 3 portions of pituitary - origins and nomenclature
- Infundibulum – stalk that connects the pituitary to the brain/hypothalamus
- Sphenoid bone – surrounds the pituitary gland
Posterior pituitary – nervous tissue
a. Extension of the neural tissue
- Directly connected to hypothalamus
- Neural embryonic origin
b. Nomenclature
- Pars nervosa
- Neurohypophysis
Anterior pituitary – glandular origin
a. True endocrine gland of epithelial origin
- Trophic hormones typically stimulate production of hormones within ant pit
b. Nomenclature
- Pars distalis
- Adenohypophysis
Intermediate pituitary – pars intermedia
a. Disappear in humans by the time were born
- Play a larger role in nonhuman animals
- Mainly produces alpha melanocyte stimulating hormone (MSH)
Posterior pituitary anatomy
- what kind of release
Neuroendocrine system between the hypothalamus and posterior pituitary
Cell bodies originate in the hypothalamus -> axons extend through infundibulum and terminate in post pit
a. Hypothalamus synthesizes posterior pituitary hormones in 2 major nuclei
• Paraventricular nucleus – mainly oxytocin
• Supraoptic nucleus – mainly vasopressin
b. Both nuclei can synthesis vasopressin and oxytocin incase of dysfunction in one
Posterior pituitary releases hormones on demand – regulated
- Regulated release – most hormones; only released when required
- Constitutive release – more rare; constant release
Neurophysins
Neurohypophysial peptides
Structure of AVP and OT
- Brattleboro rats
Neurophysins – carrier proteins of OT and AVP synthesized in hypothalamus
a. Neurophysins and proteolytic enzymes are packaged into vesicles and transported down through the axons of nuclei
- Stored in secretory granules within axon terminals until stimulated to release
Neurohypophysial peptides are released from post pit
a. 2 types of nonapeptides (9 AA) – oxytocin (OT) and vasopressin (AVP)
i. Similar structures
• Ile and Phe differ
• Leu and Arg differ
ii. Different functions & release mechanisms
OT and AVP are closely related but one can function without the other
Ex. Brattleboro rats – genetically diabetic insipidus
- Diabetes – “running through”
a. Diabetes mellitus - glucose in urine causes increases in urine production due to osmotic mvmt of water
- Mellitus – “honey”; sweet to the taste due to glucose
b. Diabetes insipidus - lack of vasopressin (same as antidiuretic hormone)
- AVP/ADH – allows the uptake of water back into the body in the kidney
- Insipidus – sour to the taste
Vasopressin
- nomenclature
- release sources
- action
- dieresis vs anti-dieresis
Nomenclature
o Arginine vasopressin
o Antidiuretic hormone (ADH)
Release is stimulated by decrease in ECF volume – 2 sources
1. Due to water loss
a. Reduced ECFV -> increased plasma osmolarity (more salts) -> fluid moves into ICF and triggers osmoreceptor activity (detect changes in osmotic pressure) -> increased AVP release from post pit
• Ex. sweating – loss of water volume causes increase in plasma osmolarity -> water moves into cells to maintain concentration and triggers osmoreceptors
2. Due to blood loss
a. Decreased left arterial volume in cardiac cycle -> decreased arterial BP -> trigger baroreceptors -> increased AVP release from post pit
Action - targets kidney
- Increases water resorption in renal tubules
- Diaresis – increase in urine flow rate
- Anti diaresis – reduction in urine flow rate (hence antidiuretic); retention of water in body - Causes vasoconstriction in vascular smooth muscle
- Maintains blood pressure if there is blood loss
Oxytocin
- release
- action
Release is stimulated by
o Birth canal distension - increased OT
o Infant suckling - increased OT
Action - positive feedback
o Increased uterine/myometrium contraction during birth
o Increased milk ejection from mammary gland
Behavioural aspects of OT and AVP
Oxytocin
1. Rats
a. Increases maternal behaviour – estrogens need to be present
2. Humans
a. Plasma OT levels increase during sexual arousal in both sexes
• May be linked in transport of sperm through reproductive tract due to increased levels in males and females
3. Acts as a strong neuromodulators in the brain – influence social recognition, memory and affiliative behaviours such as “pair bonding” (rodent research)
a. Neuromodulators – oxytocin resets balance (similar to estrogen)
b. Pair bonding may be related to OT release during let down reflex of mammary glands – pair bonding occurs during this process
Vasopressin
1. Stimulates release of ACTH (adrenocorticotropic hormones) -> synergistic with CRH -> increases cortisol (due to stress)
2. Rodent research – seems to play a greater role in males than females in social recognition and consolidation of social memory (rodent research)
a. Involved in aggression, courtship, scent marking, and learning
• Research is done on tetrapods – related to link between AVP and fluid balance (water)
o you need to protect your water resource as a land animals – links to aggression in rodents
Anterior pituitary
- anatomy
- cell types
Neurosecretory neurons release tropic hormones into median eminence – releases into hypophyseal portal blood supply
1. hypophysiotropic hormones – tropic hormones released from the hypothalamus into capillary bed that regulate the ant pit
2. portal capillary bed - capillary bed flows directly into another capillary bed
a. first capillary bed at median eminence
b. second capillary bed at anterior pit
• blood vessels are surrounded by different cell types within ant pit that synthesize and release different hormones depending on trophic hormone in capillary bed
3. non portal supply: arteriole -> capillary -> venule
adenohypophysial cells – cells surrounding blood vessels; release hormones into the capillary bed and blood stream
1. histological and cytological methods have provided definitive evidence on the cellular source for each hormone released from the adenohypophysis
a. types of staining
• basophil – basic staining
• acidophil – acidic staining
cell types and staining characteristics
1. Corticotroph cells - adrenocorticotropic hormone (ACTH)
• Basophil
2. Thyrotroph cells - thyroid stimulating hormone (TSH)
• Basophil
3. Gonadotroph cells - FSH & LH
• There are cell types that release both and some that release only one or the other
• Basophil
4. Lactotroph cells - prolactin (PRL)
• Acidophil
5. Somatotroph cells - growth hormone (GH)
• Acidophil
Anterior pituitary axis
- axis’s from anterior pituitary
- what axis are under stimulatory and inhibitory control
Hypothalamus
o Release hypophysiotropic hormones into hypophyseal portal blood supply can be stimulatory or inhibitory
Endocrine axis – connects the hypophysiotropic hormones anterior pit hormones final hormone (often stimulates synthesis and release of other hormones)
1. Cortisol release axis
a. High CNS has stressor
b. Hypothalamus synthesizes and releases CRH -> released into medial eminence and hypophyseal blood supply -> stimulates ant pit
c. Anterior pit releases ACTH -> released into bloodstream -> stimulates adrenal cortex
d. Adrenal cortex releases cortisol
i. Cortisol regulates its own release
o Long loop -> cortisol inhibit release in hypothalamus, ant pit, and higher CNS
o Short loop -> ACTH inhibits release from ant pit and hypothalamus
- Thyroid hormone axis
a. Hypophysiotropic hormone -> thyrotropin releasing hormone (TRH)
b. Ant pit hormone -> thyroid stimulation hormone (TSH)
c. Thyroid gland -> releases thyroid hormones (T3 and T4) - Androgen and estrogen axis
a. Hypophysiotropic hormone -> gonadotropin releasing hormone (GnRH)
b. Ant pit hormone -> FSH and LH
c. Gonads (ovaries and testes) - androgens and estrogens - Growth hormone/IGF axis
a. Hypophysiotropic hormone -> growth hormone releasing hormone (GHRH)
b. Ant pit hormone -> growth hormone (GH)
c. Target cells -> IGF’s
• Liver and other tissues are targeted
All axis have inhibitory and stimulatory factors – generally under control of one or the other
1. 4 main axis under stimulatory hypophysiotropic hormones – typically require stimulatory factors
a. GnRH - stimulates release of LH and FSH in ant pit
b. CRH - stimulates release of ACTH in ant pit
c. TRH - stimulates release of TSH in ant pit
2. 2 main axis under inhibitory – dominant signal that regulates release is inhibitory -> require lack of inhibition in order to activate stimulatory regulators and release hormone
a. Growth hormone
• Somatostatin – prevents production of GHRH
o Lack of somatostatin -> allows release of GHRH -> allows release of GH
b. Prolactin
• Dopamine – inhibits production of prolactin releasing hormone
o Lack of dopamine -> allows production of prolactin
Many hormones have metabolic actions in final effects -> regulation of energy
Adenohypophysial hormones
- 10 hormones secreted by anterior pituitary (type of hormone)
- structural characteristics of each family
The anterior pituitary produces 10 polypeptide hormones (FLAT PG)
o FSH, LH, ACTH, TSH, PRL, GnRH
2 families
1. GH and prolactin – similar structure family
a. Growth hormone – well conserved in vertebrates
• Any mutations throughout evolution have not been tolerated
• AA sequence in humans will be similar to that of fish
b. Prolactin – lots of variability
• Same gene expresses different variants – normal (mammalian), cleaved, spliced
- Glycoprotein family – similar structure
a. Named due to the large % of carbohydrate moieties – up to 33% by weight are carbs
b. Types
• Follicle stimulating hormone (FSH)
• Luteinizing hormone (LH)
• Thyroid stimulating hormone (TSH)
• Human chorionic gonadotropin hormone (hCG)
c. Each has alpha and beta subunit
i. Alpha unit - AA sequence is similar between hormones
- Mutations have not been tolerated in evolution
ii. Beta unit – varies between hormones
- Functionally differentiates the types of hormones
Ex. hCG – spikes early in pregnancy; pregnancy tests target these levels
• Pregnancy tests would give pos tests to everyone if it targeted alpha subunit
Pars intermedia
- regulation of POMC
Many animals have an anatomically separate pars intermedia
- By the time humans are born – has disappeared
a. During embryonic development - aMSH is produced by pars intermedia
b. As adults - cells are not anatomically distinct but still synthesize and secrete aMSH (often considered part of anterior pituitary)
Predominant endocrine product is αMSH – humans produce this in the ant pit
1. Precursor peptide -> pro-opiomelanocortin (POMC)
a. POMC is also involved in regulating food intake
b. POMC -> ACTH -> aMSH
• aMSH is derived from AA sequence of ACTH which is an AA sequence of POMC
• one POMC can’t synthesize and release ACTH and aMSH simultaneously
2. aMSH functions – pleotropic hormone (many functions)
a. melanin synthesis
• melanocytes regulation (skin pigmentation) – this is how it was first identified and named for
b. anorexigenic – inhibit food intake; regulates energy balance
c. immune responses
3. All occurs intracellularly in ant pit
a. Different cell types will express proconvertase enzyme
i. PC enzymes 1, 2, & 3 -> responsible for chopping up POMC depending on signal received
o requiring reduction in food intake – will release aMSH
o stress response – ACTH
ii. higher signal dictate activity of proconvertase enzymes
Normal growth types
- growth is influenced by
Normal growth types
- Anabolic processes – protein, fat and cartilage synthesis
- Cell proliferation
a. Hyperplasia – increase in numbers
b. Hypertrophy – increase in size - Bone lengthening
a. Increased extracellular matrix
b. Occurs a lot during puberty to reach genetically resolved height - height achieved assuming adequate nutrients
Normal growth is influenced by
- Genetic resolve
a. Reliant on proper nutrients – especially in fetal development and early life history (1-4yr old) - Diet and nutrient transfer
a. If malnourished children increase nutrient intake as they grow – can correct; creates opportunity to address possible impacts on growth and reach genetic resolve - Disease and stress
a. If it occurs in early life – will often result in not reaching genetic resolve - Multiple layers of hormonal control -> dictates individual tissue growth and whole body growth
a. Ex. brain (individual), height (whole body)
Growth rate throughout life
- what increases during puberty and what are the sources
Neonatal growth occurs under the influence of placental hormones
After birth
o Brain – fairly developed by age 10
o Height – a lot in early life and again in puberty
Pubertal growth – GH levels increase dramatically
- Associated with gonad development in males and female
a. Androgen production
i. Males – testicular androgens are very important and increase dramatically during puberty
ii. Females – adrenal androgens increase
- Adrenal gland is important for female development – lack testes
- Adrenal androgens - dehydroepiandrosterone (DHEA)
- Play large role in development of secondary sex characteristics in females
b. Testosterone and estrogen both ultimately “put the brakes on” once genetic resolve has been achieved
Hypothalamic pituitary hepatic axis
- terms
- hormones released by each structure
- GH size and abundance
- when does it secrete
- triggers for release of hormones
- how is GH transported
Terms
o Somatostatin GHIH
o Somatotrophin GH
o Somatomedins IGF’s (insulin like growth factors)
Hypophysiotropic hormones (hypothalamus/higher neural centers)
a. Growth hormones releasing hormone (GHRH) -> stimulates production of GH
b. Somatostatin (growth hormone inhibiting hormone) -> inhibits production of GH
- Dominant regulatory hormone
Anterior pituitary - secretes somatotrophin (GH)
1. GH is produced in somatotrophs (adenohypophysial cell)
a. GH is a 191 amino acid long polypeptide (large)
b. It is the most abundant adenohypophysial hormone
• 4-10% of the wet weight of the gland (~ 5-10mg)
2. Functions in
a. General anabolism
b. Height and growth
3. Spontaneous secretion over a 24 h period
a. Usually peaks in the first 90 minutes of sleep – many repair mechanisms regulated by GH while we sleep
Triggers for release of GHRH and GHIH
1. GHIH - Exercise, stress and decrease in blood glucose
a. GHIH (somatostatin) - Inhibits GH release from ant pit & downstream affects
2. GHRH - Increase blood AA or fatty acids
a. GH (somatotropin) affects
i. Liver – promotes somatomedins (IGF’s)
o IGF’s - facilitates many actions of GH
- Implicated in increased cell division, protein synthesis, and bone growth
ii. Metabolic activities not related to growth
- Energy balance - Increased fat breakdown and decreases glucose uptake by muscle cells
- Increases concentration of glucose and FA in circulation to maintain homeostasis
- Mobilizes energy resources
GH is transported in plasma attached to one or more binding proteins
o Hydrophilic – still requires and binds to proteins
The somatomedin hypothesis
- types of somatomedins
- when were IGFs identified and how
- affects of IGFs
- insulin and IGF similarities - what are dimers attached by
“Growth hormone does not have a direct effect on growth of any given tissue but rather acts indirectly through somatomedins”
- Doesn’t mean GH doesn’t influence growth - it does influence growth directly but is often facilitated by somatomedins
Types of somatomedins (IGF’s)
1. 2 main somatomedins – both share many similarities with insulin
a. IGF I -> 70 AA
• Largely influenced by levels of GH
b. IGF II -> 67 AA
• Influenced less by GH
2. Mainly secreted and synthesized in the liver
IGF’s were identified in early experiments – Influencing bone growth from blood samples
3 treatments in experiment
1 – serum from a hypex mouse
a. Hypex = hypophysectomy -> connection between hypothalamus and pituitary is severed
o No signals from HPH axis -> no GH or IGF hormones
b. Saw no growth
2 – added GH + serum from hypex mouse
a. Saw no growth with only GH
3 – injected hypex mouse with GH then added serum from mouse
a. Saw growth
o Indicated that GH stimulated something else that stimulated growth IGF’s
Affects of IGF’s
1. IGF I is associated with long bone growth
a. Massive increase during puberty
• GH levels increase much less by comparison
• IGF I is primary driver of growth during puberty
b. Tissue specific regulation of IGF I synthesis is evident in terms of bone growth
2. IGF II is important during fetal development
a. Plays a role in adult growth – not as much as IGF I
Insulin and IGF receptor similarities
- Both single pass (1 MSR)
a. linked to tyrosine kinase domains – enzyme of ICF triggered by binding of ligand to ECF side - Both dimers
a. Monomers are attached by sulfate bridges
Bone tissue and cell types
- anatomy of bone
- spongy vs compact
- bone modelling
Bone is living tissue – surrounded by an extracellular organic matrix; have cell types with specific roles
- Cells – important in the modulation and shaping of bone and in calcium balance
a. Osteoblasts – bone builders
b. Osteoclasts – bone breakers (crushers)
Anatomy of bone
1. Diaphysis – the mature bone shaft
2. Epiphysis – at either end
a. Epiphyseal plate – separates the epiphysis from the diaphysis during growth
• Plate is Important in growth
b. Epiphyseal line – separates epiphysis from diaphysis after maturation
Compact vs spongy bone
o Compact – outer surface of bone; dense and used for support
o Spongy/trabecular – forms calcified lattice within compact bone
Bone modelling requires constant formation (adding cells) and breaking down (removing cells)
Bone growth
- width
- length
Bone growth width – occurs throughout life
- Osteoblasts – deposit new bone matrix on the outer edges of old bond to increase width
a. Produce osteoid that provide a framework for hydroxyapatite crystals
- Osteoid – mixture of collagen, enzymes and proteins
- Hydroxyapatite crystal – inorganic components of bone tissue composed of calcium and phosphate
- Within collagen matrix - Bone width formation is a dynamic process
a. Osteoblasts - turn into mature bone cells (osteocytes)
b. Osteoclasts - model the formation as bone grows
- Bone degradation will slightly outpace construction throughout life
- Bones become more brittle as we age
Bone growth length – occurs during puberty
1. Largely governed by IGF’s
o Growing pains – painful as bones lengthen
2. Process
a. Chondrocytes – cartilage cells located in the epiphyseal plates
- Lengthen bond by dividing and multiplying – proliferative cell layer
- Older cartilage cells enlarging at the border of the diaphysis – hypertrophic layer
b. Aspects of growth
i. Hyperplasia - lots of cell division
• Causes epiphysis to move apart from each other
• Direction of growth is towards the epiphysis
ii. Hypertrophia - increase in cell size
• Occurs near diaphysis
c. Ossification – chondrocytes disintegrate and osteoblasts lay bone on top of cartilage
- Provides matric for hydroxyapatite crystals to aggregate on
Dual effector theory
- what kind of local communication with IGFs
GH and IGF I both direct proliferation and hypertrophia
GH targets cells within germinal cell layer
1. Affects
a. Increase in transcription and translation of IGF I – local production of IGF hormone
• IGF production also occurs largely in the liver
b. Increase in the development of IGF I responsiveness
• increases receptor sensitivity and affinity – more efficient
IGF I functions in proliferative cell layer and hypertrophic layer
a. Functions as autocrine and paracrine factor
b. Affects
- Promotes cell division within proliferative layer – pushes epiphysis apart
- Promotes cytoplasmic maturation and cell size increase in hypertrophic layer
Abnormal growth
influenced by the HPH axis
Normal
o GH targets liver cells - promote synthesis and release of IGF’s
o IGF’s target somatic cells - stimulates growth
Primary dysfunction - dysfunction in anterior pituitary
1. Hyperactivity – increase in activity and release of GH
a. 2 phenotypes can result – dependent on when there is an increase
• During infantry - results in gigantism
• During puberty and adulthood - acromegaly
b. People who suffer from:
• Robert Wadlow – gigantism
• Andre the giant – suffered from both gigantism and acromegaly; Very hyperactive pit gland throughout infant and lifetime
2. Hypoactivity – decrease in activity and release of GH
a. Results in dwarfism – less GH being released less action of GH targeting the liver less IGF’s
• Won’t grow to genetic resolve due to mutation
Secondary dysfunction – dysfunction between pituitary gland and liver
1. Laron dwarfism - genetic mutation
a. Village in Mexico (Loja) – everyone within that village is short in height
• Due to genetic mutation
• Doesn’t seem to affect men as much
2. Many forms - all affect IGF I
a. Lack of GH receptors on liver - not as responsive
• Leads to lack of IGF I production
b. Reduced carrying capacity due to lack of binding proteins
• Reduced affinity/abundance of GH binding protein
• Reduced affinity/abundance of IGF binding protein
Tertiary dysfunction – end organ resistance
- IGF’s may not be able to impact the actions in long bone growth
- Can be influenced directly by GH
- If communication between GH and germinal cell layer is impacted - end organ resistance
