KNPE125 UNIT 1

Physiology

Homeostasis

Homeostasis

the maintenance of relatively constant conditions for physiological variables in the internal environment

Involves detecting changes in masses within compartments and activating responses that alter inflow or outflow (or both) for that compartment.

Mass

The amount of a substance in a specific compartment

• The same substance in different compartments represents different masses (because mass is specific to compartment)

• Masses are regulated by the balance between inflow and outflow

• A change in a mass means there is an imbalance between inflow and outflow

Compartment

An area/space/container where substances exist

Inflow vs Outflow

Inflow: the rate that the substance is being added to the compartment

Outflow: the rate that the substance is being removed

• Masses may have multiple inflows and outflows

• There is always an inflow and outflow for every mass in physiology

• inflow and outflow are controlled by feedback, feed forward, and receptor mediated control

Inflow, outflow, and gradients

• inflow and outflow have their own energy gradient and conductance

• The regulated mass represents the low energy (ELO) for its inflow.

• The regulated mass also represents the high energy (EHI) for its outflow.

• Inflow and outflow each contain their own energy gradient (EHI – ELO).

• the ELO for inflow and the EHI for outflow for the regulated mass IS the regulated mass

Increase in mass can occur from…

1. Inflow increases and outflow does not change.

2. Outflow decreases and inflow does not change.

3. Inflow increases and outflow decreases.

4. Outflow increases a little but inflow increases a lot.

5. Inflow decreases a little but outflow decreases a lot.

Decrease in mass can occur from…

1. Outflow increases and inflow does not change.

2. Inflow decreases and outflow does not change.

3. Outflow increases and inflow decreases.

4. Inflow increases a little but outflow increases a lot.

5. Outflow decreases a little but inflow decreases a lot.

No change in mass can occur from…

1. Inflow and outflow do not change.

2. Inflow decreases and outflow decreases at the same time (changes in inflow and outflow are equal).

3. Inflow increases and outflow increases at the same time (changes in inflow and outflow are equal).

Flow will increase if…

1. Conductance (K) increases

2. The energy gradient (ΔE) increases because the high energy (EHI) increased

3. The energy gradient (ΔE) increases because the low energy (ELO) decreased

4. The energy gradient (ΔE) increases because the high energy (EHI) increased and the low energy (ELO) decreased

Flow will decrease if…

1. Conductance (K) decreases

2. The energy gradient (ΔE) decreases because the high energy (EHI) decreased

3. The energy gradient (ΔE) decreases because the low energy (ELO) increased

4. The energy gradient (ΔE) decreases because the high energy (EHI) decreased and the low energy (ELO) increased

Flow will not change if…

1. Conductance (K) does not change

2. The energy gradient (ΔE) does not change because neither the high energy (EHI) or low energy (ELO) changed

Control system

Exist to maintain regulated variables within a normal range

Regulated variables

Certain variables which are vital to survival. They are relatively stable (within a range), but not static (unchanging)

Homeostatic set point

Ideal point for a substance to be at.

Conservation of mass

Preservation and restoration of an amount of substance within a compartment

How are mass and flow related?

What happens when inflow = outflow?

Mass remains stable

Flow

the rate at which a mass moves from one compartment to the next or the conversion of a substance from one form to another in a metabolic reaction.

determined by energy gradient and conductance

Flow = K x (EHI – ELO)

Flow models

• Flow models are models that represent physiological flow

• arrows represent flows

• energy gradient is the difference in energy between the two sides of the arrow, the high energy at the flat end of the arrow and the low energy at the arrowhead end of the arrow

• conductance is written on top of the arrow

Energy gradient (ΔE)

the “energy” difference between the masses of two different compartments that drives flow. Can be pressure, electrical charge, or concentration gradient.

• Things tend to move down an energy gradient (high to low)

• larger gradient causes more flow

• flow continues until equilibrium is reached (ΔE=0)

ΔE = Ehi - Elo

Pressure Gradient (ΔP)

Pressure is the physical force exerted by a substance on the walls of its compartment. This gradient is created by the difference in pressure between two compartments. (PHI -PLO)

Concentration Gradient (ΔC)

This gradient is created by the difference in the concentration of a substance in one compartment compared to another compartment. (CHI -CLO) or ([HI] – [LO])

• square brackets [ ] are often used to denote the concentration of a substance

Electrical Gradient (Δe)

This gradient is created by the difference in the electrical charge, which is determined by the number of charged particles (positively or negatively charged), of one compartment compared to another compartment. (eHI -eLO)

Point of equillibrium

point in which there is no difference between the high and low energy of a gradient

no net change, there is equal rates of change in the flow in both directions

Conductance

opposite of resistance; the ease with which a mass can flow, or move, between compartments

• If resistance is HIGH, then conductance is LOW

• If resistance is LOW, then conductance is HIGH

Explain the physiology of blood flow

Blood flows from the arteries (high pressure) to veins (low pressure), the pressure gradient drives flow. The arterioles (after arteries) constrict (close) or dilate (open) to control flow and determine conductance.

Explain the physiology of membrane transport flow

The membrane transports molecules in and out of the cell, acting as a flow. The concentration gradient is the difference between molecules outside and inside the cell. The conductance is the number of transport proteins on the cell wall that can let the molecules cross the membrane.

Feedback

Detecting a change in the regulated variable, error signal is sensed and a controlled response is triggered to correct the change and return to homeostasis. Can be positive or negative.

Feed forward

Detecting a disturbance that could lead to a change in the regulated variable. Happens before the error signal is detected; can be wild and uncontrolled. Acts to anticipate a change in the regulated variable.

Feedback control loop

1. A change in the regulated variable results in altered activity of the sensor.

2. The sensor’s change in activity will be received and interpreted by the integrator.

3. The integrator alters the activity of one or more effector(s).

4. The effector(s) acts on the regulated variable to return it to it’s original state.

Integrator

what is computing the signal being sent from the sensor

Negative feedback

changes in the regulated variable are sensed and a response is triggered to bring the regulated variable back to normal (i.e. opposite direction)

Positive feedback

changes in the regulated variable are sensed and a response is triggered to continue changing the regulated variable (i.e. same direction)

Physiological example of negative feedback

Aorta is the spot where bp is sensed as blood leaves heart, when high bp is sensed, system must bring it down. Baroreceptors sense the stretch of it's walls high bp, signal is sent to brain, brain acts as integrator, heart rate is the effector, heart rate decreases to lower the high blood pressure.

Physiological example of positive feedback

Sensors are in birth canal, it recognizes that cervix pressure increases, brain is integrator, effector is pituitary glans which releases oxytocin, increasingly until child is born

Feed forward control loop

1. Disturbance is measured prior to a change in the regulated variable and is detected by a sensor

2. The sensor signals the integrator

3. The integrator alters the activity of one or more effector(s)

4. The altered activity of the effector(s) act to create a response to try and prevent a change in the regulated variable

Physiological example of feed forward

Muscle becomes flooded with calcium before movement occurs, we can prevent an ATP shortage by detecting increase in calcium and increasing the enzymes that produce ATP

Receptor mediated cellular control

Controlling effectors via the process;

1. brain (or integrator) sends a signaling molecule

2. binds to receptor protein

3. intracellular signal molecule occurs

4. target proteins are made

5. cellular response occurs

Signaling molecule acts on target proteins in the cell and proteins then carry out a response in the cell.

What are the 3 types of signaling molecules?

hormones, neurotransmitters, paracrine

Hormones

Secreted by endocrine glands (integrator) or cells into the blood. Only target cells (effectors) with receptors for the hormone will respond to the signal.

Neurotransmitters

chemicals secreted by neurons that diffuse across a small gap (synapse) to the target cell.

Paracrines

Secreted by a cell to act on a neighbouring cell (cell to cell communication) and does not travel through blood. The receiving cell must have a receptor for the paracrine.

Specificity

a receptor can only bind one kind of messenger but messengers can bind to multiple receptors (as long as they are coded for it)

Affinity

Strength of (likelihood of) messenger binding to a receptor. Larger affinity = more likely to bind to that receptor than another receptor.

Types of membrane bound receptors

Channel-linked receptors, Enzyme-linked receptors, G-protein-linked receptors

Channel linked receptors

Signalling molecule binds to receptor causing an ion channel to open/close . Changes conductance for flow of a substance into or out of a cell

Once inside ions can:

1. Change the electrical properties of the cell (membrane potential)

2. Interact with proteins inside the cell and initiate a cellular response

• A ‘closed channel’ opens when the receptor binds to allow substances to bind

Enzyme-linked Receptor

Signaling molecule binds to receptor activating an enzyme. Receptor then modifies another protein (an enzyme) activating an intracellular response.

G protein-linked receptor

Very common in our bodies and an important part of physiological regulation. When receptor is activated, GDP is exchanged for GTP, alpha subunit is released and can act on the effectors. G protein is activated to create signaling cascade.

• G Proteins have 3 subunits: ⍺, β and γ

• ⍺-subunit bound to GDP

• When the receptor is activated, GDP is exchanged for GTP

• ⍺-subunit released, and acts on effectors

What are the 3 types of G protein linked receptors?

1. Channel Affecters: The alpha subunit acts directly on slow ligand gated ion channels to open or close them

2. Stimulatory: Activate amplifier enzymes (enzymes that catalyze the production of a second messenger)

3. Inhibitory: Inhibit amplifier enzymes

Secondary messengers

Molecules acting in between the signaling molecule and the target response

Cell

location of all basic function. in essence fat globules in water with the inside of the cell separated from the rest of the body.

Cytosol

the largest area of the cell that is considered ‘empty space’. It contains the organelles.

Endoplasmic reticulum

Organelle made up of a network of lipid membrane, forming an intracellular compartment that is separate (distinct storage) from the cytosol.

• Calcium handling in muscle (release of calcium from sarcoplasmic reticulum); the calcium can be released from ER in the cell upon contraction

• Important for intracellular signalling; movement of proteins that are synthesized in ER to other areas of cells

• Adjacent to the nucleus; allows for transport of mRNA and nuclear info from nucleus to ER

Granular Endoplasmic Reticulum

AKA rough ER, covered with ribosomes to act as the site of protein synthesis (mRNA translation at ribosomes)

Smooth ER

responsible for intracellular transport (from ER to golgi) and lipid synthesis (forming membranes)

Golgi Apparatus

forms a network with the ER, responsible for transport of substances from the ER to other parts of the cell.

Involved in budding, fusion, and vesicles

Budding, fusion, and vesicles

• ‘Stuff’ moved from golgi apparatus to other areas of the cell via ‘budding’ and ‘fusion’

Budding: formation of a vesicle from the membrane on the golgi via blubbing (formation of a bubble on the membrane) eventually turning to an independent vesicle that integrates the membrane protein into the cellular membrane and expels waste product to extracellular space

• Integral membrane proteins go on the membrane of the vesicle, waste product goes inside the vesicle

Fusion: opposite of budding, attachment of the vesicle to the cell membrane upon contact

Summary of cell transport

Substances formed in the ribosomes in ER, vesicle transport moves substances from ER to Golgi, vesicles more from Golgi to target area where substance is needed

Mitochondria

contains an inner and outer membrane, creating in intra-membrane space called the matrix, with the foldings of the inner membrane being called cristae.

• produce ATP (powerhouse of the cell)

  • inner mitochondrial membrane has ETC where H+ is pumped

• recent evidence that mitochondria form a network that allows for transport

• Tends to be localized around areas of the cell that use energy (i.e; muscle cells)

• Mitochondrial DNA is an index of mitochondrial content

Mitochondria and exercise

• Mitochondria increase with exercise training

• More mitochondria = more ATP = greater exercise performance

Mitochondria and health

• Fatty acid can be oxidized by mitochondria or stored, evidence that storing fat in muscle impairs insulin signaling, causing type 2 diabetes

• More mitochondria metabolism, there is lower fatty acid storage, and higher insulin sensitivity

Nucleus

component of cell containing genetic material, consists of nuclear membrane, nucleoplasm, and nucleolus. Dictates cell type and function.

• Location of DNA (controls protein synthesis)

• Nuclear membrane is continuous with ER (allows RNA direct access to ribosomes)

Nucleolus

location of transcription in the nucleus, initiation of protein synthesis

Organization of the cell

Chemical reactions

Formation of new substance(s) (product) from existing one(s) (substrate). There are 2 types; require energy or produce energy.

Free energy

amount of energy a molecule contains

Free energy change (∆E)

change in free energy following a reaction

∆E = Free energy in products – Free energy in substrates

Endergonic

Require energy to proceed (positive ∆E)

• Must be coupled to exergonic reaction (cannot occur spontaneously)

• ENDER energy ENTERS

• ex; photosynthesis

• most reactions are endergonic

Exergonic

Give off energy (negative ∆E)

• Can occur spontaneously

• EXER energy EXITS

• ex; lighting a match

ATP vs ADP

When high energy bonds are broken; ATP goes to ADP + Pi. This releases energy that is the underlying energy source for cellular work.

The energy required for reforming ATP comes from the breakdown (metabolism) of fat, carbohydrate, and protein

• Regulated variable; amount of ATP

• Masses: ATP and ADP + Pi

• Inflow; amount of energy needed for cellular work

• Outflow; amount of ATP broken down

Activation energy

Most exergonic reactions do not occur spontaneously, even for exergonic reactions energy is required before a reaction can start

Enzymes

Large high specific proteins that act on substrate to convert them to product and catalyze chemical reactions.

• decrease activation energy and increase the rate of reaction without changing net change in free energy

• determines conductance

• Specific binding sites for specific substrates

• These reactions would occur spontaneously at a slower rate

Enzyme-substrate binding

Enzyme brings pieces closer together so we can achieve the product. Enzymes facilitate the combining of substrate and thus decrease energy required to initiate reaction. it occurs at the active site.

How efficient are enzymes?

• In general, enzymatic reactions take between 0.02 and 0.002 seconds.

• ~10^15 times faster than the reaction would proceed spontaneously

• 1000000000000000 times faster or 1 quadrillion times faster

what is Vmax and why does it occurs?

Maximum velocity a reaction can proceed

At a certain point no matter how much substrate you add the reaction will not speed up because all enzymes are occuppied.

Michaelis Constant (Km )

Substrate Concentration required to meet ½ V max

How do enzymes increase rate of reaction?

• Higher probability that the substrate will end up at the enzyme or the appropriate substrates will end up together

• Increasing the Ehi for the flow

• increasing amount of substrate will increase the rate of reaction (more ability to bind to enzyme)

• increasing amount of enzyme will increase the rate of reaction (more binding sites available), increases conductance

Saturating substrate

At a certain point no matter how much substrate you add the reaction will not speed up (Vmax). If all enzymes/conductance's are active increasing substances will not increase the rate of reaction.

What is the flow model of enzymes?

Substrate affects the energy gradient, enzyme affects conductance

Transcription

Production of RNA from DNA in the nucleus. Endergonic process.

DNA

Deoxyribonucleic Acid; Contains information to make every protein in the body. Has a double helix shape with each strand containing 1000’s of gene.

• There's a full copy of your DNA in every cell

• Every cell has the same DNA, but how the DNA is used and which proteins are made determines cell function

• Each protein is coded by a specific area of DNA

Gene

Contains the encoded information to form a single protein

Promoter

where the activation of gene is controlled

Coding region

contains the information to make protein

3 types of protein action

1. Repressor protein: inhibits coding of gene

2. Activator: activates coding of gene

3. Negative feedback: if gene is copied and used a lot, it binds to it's own promoter to slow it's own production to prevent overproduction of the product

Transcription steps

1. Polymerase (The Zipper) binds to promoter, when bound gene becomes active, when active, RNA is made.

2. As polymerase moves down coding region the two strands of DNA are separated

3. separated strand is transcribed and a strand of RNA is formed (Exact copy of DNA). Formation of RNA requires ATP.

4. The polymerase moves to the end of gene and unbinds. DNA is put back together. Result is RNA strand.

Types of RNA

Messenger RNA (mRNA): copy of DNA used to form new protein

Transfer RNA (tRNA): brings building blocks (amino acids) to ribosome 60s subunit during translation to create polypeptide chain.

Ribosomal RNA (rRNA): forms most of a ribosome

Translation

Endergonic process of producing protein from mRNA, happens in the ribosomes of the ER. Binding of amino acids together to form a new protein.

• mRNA codes for a specific sequence of amino acids that determines protein function

• Amino acids are brought to the ribosome by tRNA

Ribosome structure

Ribosome is made up of 2 parts:

1. 40 s subunit: binds mRNA

2. 60 s subunit: builds and releases protein

• Both subunits are made up of rRNA

Translation steps

1. Initiation: mRNA is bound to the 40s subunit, with the use of energy from ATP, mRNA starts to move through the ribosome

2. Elongation: As mRNA moves through ribosome, protein is formed

3. Termination: When the end of the mRNA is met, the newly formed protein is released. This also uses ATP.

4. New protein moved to its proper cellular location and contributes to cellular function

Protein synthesis flow

• Protein content is mass

• Protein synthesis is inflow

• Protein breakdown is outflow

Ricin

Ricin is a substance that inhibits ribosomes and protein synthesis, so decreases the inflow to protein content.

• Leads to malfunction because no new proteins replace the broken down proteins

• Cell eventually dies, and organism does too

The training effect

• An acute bout of exercise increases the rate of mitochondrial transcription; causes increased mRNA for protein involved in ATP production

• An acute bout of exercise increases mitochondrial translation capacity; causes increased proteins available to bind to mRNA and stimulate translation

• overall; more protein synthesis = more protein/enzyme = greater function of mitochondria = more ATP = better exercise performance

Cell membrane

cells are surrounded by a phospholipid bilayer that provides barriers between inside and outside of cells. Phospholipid Bilayer forms a hydrophobic barrier between inside and outside of cell

Phospholipids

composes membranes; phosphate head is hydrophilic, fatty acid tail is hydrophobic.

Hydrophobic vs hydrophyllic

Hydrophobic: Repels water (does not dissolve). Lipid portion.

Hydrophyllic: Dissolves in water. Phosphate portion.

What can and can’t pass the phospholipid bilayer?

• Water soluble substances don’t pass (Carbohydrate, Protein, Ions); allows content to be controlled, but can be transported by channels that are always open.

• Fat soluble substances do pass (Oxygen, Carbon Dioxide)

What are the two types of simple diffusion?

1. membrane is permeable for substances to pass (fat soluble)

2. diffusion through channel proteins that are always open (water soluble), so no work needs to be done

Fat transporters

Until recently it was generally assumed that fat uptake into tissue was achieved by simple diffusion, when actually occurs via facilitated diffusion.

Facilitated diffusion

Accomplished by transport proteins via conformational change (work must be done, but energy is not used). Maximal rate of transport limited by number of transporters.

Diffusion across membranes is flow. The flow will plateau eventually if all the channel proteins are being used.