Exam #1 Flashcards
what is physiology?
The study of normal functioning of a living organism and its component parts
- structure and function relationships
- includes chemical and physical interactions
- emergent properties (properties of a system that are a result of non-linear interaction between component parts
what are the 4 things that characterize “living” things?
1) It is made up of one or more cells
2) Regulates its internal environment
3) Responds to stimuli (sensory systems to detect it)
4) Capable of reproduction (self replication)
- this excludes viruses as living things
what are the 10 levels of organization of life
1) Biosphere
2) Ecosystem
3) Population
4) Organism
5) Organ system
6) Organ
7) Tissue
8) Cell
9) Molecule
10) atoms
why is physiology important?
1) Leads to treatment of diseases in humans and other organisms (pathophysiology)
2) Helps us understand how organisms cope with environmental stressors
3) Foundation of understanding the philosophical question “what is life?”
4) Required credit for certain programs
what are 5 themes in physiology?
1) Structure and function and how they’re closely related
2) Homeostasis and control systems
3) Information flow coordinates body function
4) Need for energy
5) evolution
homeostasis
The ability to maintain a relatively constant internal environment even when the external environment is variable
Give examples of what parameters of an animal must be regulated to within certain levels in order to support life
- temperature
- pH
- salinity
- oxygen, carbon dioxyde
- nutrients
what is the role of a control system in regards to homeostasis?
A control system monitors and adjusts regulated variables (internal temp, pH, etc.)
biomolecule
Organic molecule that is commonly associated with life
-carbohydrates, lipids, nucleic acids, protein
what is the general formula of a carbohydrate?
C(n) H(2n) O(n)
what are 3 properties of carbohydrates?
- most are hydrophilic (lipophobic)
- very abundant in nature (most common molecule)
- used for structure and energy
- almost all eukaryotic cells can use glucose for energy and can store some form of glucose (monomer or polymer) for energy
- Plants and arthropods use carbohydrates as structural molecule
- many proteins and lipids are modified by the addition of carbohydrates
Simple sugars
-most common ones are building blocks of complex carbohydrates and have either 5 or 6 carbons (ribose and glucose)
monosaccharides
Consists of glucose and another monosaccharide
Examples: sucrose, maltose, and lactose
disaccharide
True or False?
Nucleotides are involved in energy metabolism and signaling
true
nucleotide
Consists of one or more phosphate group, a 5 carbon sugar, and a nitrogenous base
another word for nitrogenous base
“r” group
The structure of the nitrogenous base determines whether the nucleotide is ________?
- adenosine
- cytosine
- guanosine
- thymidine
adenosine triphosphate (ATP)
Basics molecule of energy storage in most organisms, including mammals
guanosine triphosphate (GTP)
Energy source in many physiological chemical reactions
Are lipids generally hydrophobic or hydrophilic?
hydrophobic (or have parts that are hydrophobic)
what are the 5 groups of lipids?
1) Fatty acids
2) Glycerides
3) Phospholipids and sphingolipids
4) Steroids
5) Eicosanoids
lipids are general comprised of what?
-contain mostly carbon and hydrogen, a few oxygen atoms, nitrogen, and phosphorus
what are the 3 roles of lipids?
1) Structure of cells
- waterproof: keep insides in and outsides out
- pliable
2) Energy source
3) Communication (within and between cells)
a fatty acid is comprised of what?
Long unbranched hydrocarbon chain with 8-28 carbons
-has carboxyl (=acidic) functional group
Saturated fats have _____ and unsaturated fats have ______
no double bonds, double bonds
The more double bonds an unsaturated fat has, the _____ likely it will be solid at room temperature
less
glycerides are a derivitive of _____
fatty acids
What is the most common fat molecule in your body?
triglycerides
What is the difference between monoglycerides, diglycerides, and triglycerides?
the number of fatty acid tails
Phospholipids are a derivative of _____
glycerides
What is the major component of cell membranes?
phospholipids
what are phospholipids comprised of?
A diglyceride, a phosphate group, and a variable “R” group
phospholipids are amphipathic molecules, what does this mean?
having both hydrophilic and hydrophobic parts
- they have polar heads and non-polar tails
- the “R” group is a variable polar group
Phospholipid bilayer:
Micelles are:
Liposomes have:
1) Forms a sheet
2) Droplets of phospholipids
3) An aqueous center
What is the difference between phospholipids and glycolipids?
glycolipids are decorated with a carbohydrate (glycophospholipid)
what are steroids?
- basic structure consists of 3 6-carbon rings plus one 5-carbon ring (17 carbons)
- different functional groups (“R” groups)
- play roles in communication and cell structure
eicosanoids
- main chain consists of 20 carbon atoms
- many are derived from the fatty acid arachadonic acid
- main function is communication within cells and between cells (inflammation, pain, platelet aggregation)
- primarily lipophilic (hydrophobic) but small [] can dissolve in
what are proteins?
- macromolecules
- linear chains of amino acids
How many amino acids are encoded by the universal genetic code?
20
how many amino acids are essential? how can we obtain these?
-2 additional amino acids can be incorporated other than the 20, 9 are essential, we need to consume them because our body cannot synthesize them
A short chain of amino acids is called a _____
peptide
Longer chains of amino acids are called_____
proteins
Proteins have complex structures that are determined by _____
the sequence of amino acids that make them up, this sequence which is encoded in the genome
what is the primary structure of amino acids?
the sequence of amino acids
what is the secondary structure of amino acids?
Has to do with the interaction of amino acids
what is the tertiary structure of amino acids?
has to do with the way they react with eachother
what is the quaternary structure of amino acids?
interaction of multiple sub-units
proteins are the tools of the cell, explain what this means
- proteins are versatile, and carry out many different jobs
- in every mammalian cell, there are 10,000-15,000 different proteins expressed
explain the differences between fibrous and globular proteins
Fibrous -insoluble -generally used for structure Globular -usually soluble -7 different
name the 7 different kinds of soluble proteins
1) Enzymes
2) Membrane transporters
3) Signal molecules
4) Receptors
5) Binding proteins
6) Regulatory proteins
7) immunoglobulins
In order to do something a protein must interact or bind with _____
other proteins, molecules, or ions
A molecule that binds to a protein binding site is called a_____
ligand
An ______ ligand is something natural in your body: ex: hormone or neurotransmitter
A _______ may be a drug or a toxin
endogenous, non-endogenous
A protein binds a ligand with affinity, what does this mean?
high affinity means it will bind tightly, weak affinity means it will bind weakly
what is an agonist?
A ligand that binds to a protein binding site and alters the state of the protein, resulting in a biological response
-a hormone or neurotransmitter or a drug for example
what is an antagonist?
A ligand that reduces the action of an agonist (binds but causes no biological response)
what are the 2 different types of antagonists? what is the difference between the 2?
1) Competitive: act to block the agonist at its binding site
2) Allosteric: act to block the agonist by binding to the protein away from the binding site and inactivate the binding site
How do we measure the rate of a protein?
Protein activity has a measurable rate
- often depends on amount of protein and [ ] of ligand
- has a maximum rate (saturation)
The more protein present the ____ the rate of activity (when the ligand remains constant)
faster
If the amount of _____ is held constant, the reaction rate depends on the amount of ligand, up to the ______
-like an elevator, only room for so many people until max capacity is reached
binding protein, saturation point
what are 4 factors that can alter protein binding?
1) Isoforms (closely related proteins)
2) Activation (sometimes proteins need to be activated/altered somehow)
3) Physical factors (pH, temperature; these can cause structural changes, protein may become denatured)
4) Modulation
- covalent modification (phosphorylation, dephosphorylation, addition of lipid or carbohydrate)
- agonists, antagonists
what make up amino acids?
All amino acids have a carboxyl group (COOH), an amino group (NH2), and a hydrogen attached to the same carbon
-the 4th bond of the carbon attaches to a variable “R” group
what are the 4 functions of a cell membrane?
1) Physical barrier (separates ICF from ECF)
2) Gateway for exchange (movement of solutes, semipermeable)
3) Communication (home to receptors that detect physical and chemical stimuli and starts cascade of response to stimuli)
4) Cell structure (membrane proteins hold cytoskeleton proteins to give cell structure, may also form specialized junctions)
what is the cell membrane comprised of?
- made of mostly proteins and lipids
- ratio of protein to lipid is different for different cell types
- more active cells tend to have more proteins
what is the fluid mosaic model of the membrane structure?
- proteins area float on a sea of lipid
- some proteins are anchored, some of them are free to diffuse around or “float” around on the sea of phospholipids
what kinds of lipids make up the structure of a cell membrane? what kinds of proteins?
Lipids: glycolipids, phospholipids, cholesterol, sphingolipids
Proteins: integral, peripheral, cytoskeletal, extracellular matrix
cell membranes: phospholipids
- mostly comprised of phospholipids
- several different varieties of these (R-group saturation)
- polar head groups towards aqueous side, non polar fatty acid tails inside
what alters a cell membranes fluidity?
cholesterol
cell membranes: cholesterol
- flat molecule, slips between fatty acids
- regulates membrane fluidity
- slows diffusion of molecules across membrane
cell membranes: sphingolipids
- have longer tails than phospholipids
- tend to aggregate together = lipid rafts
- rafts also have a high density of cholesterol
- some proteins associate ONLY with lipid rafts, leading to areas of specialization on cell membranes
- ex: some G-protein coupled receptors
- errors in lipid rafts composition is thought to play a role in development of some diseases such as Alzheimer’s
cell membranes: proteins
- integral (has been modified)
- polytypic = transmembrane
- monotypic = permanently associated from one side
- peripheral (easy to separate)
cell membrane: integral proteins (transmembrane)
- permanently attached to the cell membrane
- integral polytypic = transmembrane proteins
- span the lipid bilayer once or several times
- approximately 20-25 hydrophobic amino acids to span the membrane
cell membrane: integral proteins (monotypic)
-permanently attached to the cell membrane
-monotypic proteins = permanently attached to membrane from one side
A) lipid anchored proteins
-modified by the addition of a fatty acid
-often associate with lipid rafts
B) may have strongly hydrophobic sections that allow it to associate with lipid portion of bilayer
_____ associate non-covalently with integral proteins, or polar heads of phospholipids
peripheral proteins
cell membranes: proteins
cytoskeleton
- not a membrane protein, but often interacts with membrane proteins
- flexible 3-d skeleton of fibrous proteins throughout the cytoplasm (contribute to cell shape)
cell membrane proteins
extracellular matrix
- membrane proteins and secreted protein found on the extracellular side of cell membranes
- forms a husk around cells
- highly variable glycosylation (modified by the addition of carbohydrates)
- contribute to cell strength (defines how far a cell can be stretched - ex: muscle cell)
muscular dystrophy
look at required reading for more detail
- dystrophin provides a link between cytoskeleton and extracellular matrix
- in MD, this protein is missing (or non-functional)
- results in easily damaged muscles, in severe forms, repeated damage causes muscles to eventually waste away
diffusion
- the process of moving solute molecules away from an area of high concentration towards area of low concentration
- “down the concentration gradient”
- passive
- no external energy is needed, just kinetic energy of the molecules
- this process continues until equilibrium is reached
what things can affect the speed of diffusion?
Diffusion is fast over short distances and slow over long distances
- the time taken to get from A to B is a "distance squared" relationship: if distance doubles from 1 to 2, time increases from 1 to 4 (=2 to the power of 2) - rate of diffusion is faster at high temp - rate of diffusion is faster for small molecules - rate of diffusion is slower across a membrane
simple diffusion
-no membrane, diffusion is fast
semipermeable membrane
-allows selected solutes to pass, but more slowly
Why does the type of molecule influence the diffusion across the cell membrane?
1) Could be because of the size
2) Could be polar or non-polar
Give examples of hydrophobic, non polar molecules that diffuse across a cell membrane
- O2, CO2
- lipids
- steroids
- fat soluble molecules
- these diffuse freely, almost unimpeded
can small uncharged molecules diffuse across the cell membrane?
- urea
- H20??
- there are channels in the cell membrane that allow water to move across, but can also diffuse freely
can large uncharged molecules diffuse across the cell membrane?
- glucose, proteins, amino acids
- very big molecules and are not charged, do not diffuse across, interact with the aqueous environment
can charged molecules diffuse across the cell membrane?
- ions
- cannot diffuse across, need transport proteins
what 5 things affect the diffusion of a molecule across the cell membrane?
1) The type of molecule
a. Size
b. Lipid solubility: polar or non-polar
2) Concentration gradient
3) Temperature
4) Surface area
a. More surface area, faster diffusion
5) Composition of membrane
a. Simple bilayer vs many proteins and extracellular matrix (simple bilayer relatively easy for molecules to diffuse across
b. Types of phospholipids and sphingolipids (if these have a lot of double bonds, all the molecules are more spaced apart
c. Presence of cholesterol (a lot of cholesterol is able to block molecules from diffusing between
what is fick’s law of diffusion?
Rate of diffusion is proportional to the surface area x concentration gradient x membrane permeability
Membrane permeability is proportional to the lipid solubility divided by the molecular size
liposomal drug delivery
- some drugs may have low bioavailability due to poor solubility
- some drugs may be toxic at useful doses, and must be targeted to a specific cell type (may work well for some problems, but could be dangerous to other organs)
- liposomal drug delivery could be useful to fix these problems
how does liposomal drug delivery work?
- surface proteins to target liposome to specific location in the body
- surface sugars to prevent destruction by the immune system
- oil-soluble drugs in the lipid bilayer
intracellular fluid
-2/3 of the total body water volume. Material moving into and out of the intracellular fluid must cross the cell membrane
extracellular fluid
Includes all the fluid outside the cells. The ECF is 1/3 of the body fluid volume
- consists of:
- intersitital fluid, which lies between the circulatory system and the cells, is 75% of the ECF volume
- plasma, the liquid matric of blood, is 25% of the ECF volume
homeostasis is synonymous to equilibrium
True or False?
false
- there is chemical disequilibrium in homeostasis
- electrical disequilibrium
- there is osmotic equilibrium (no net movement of water)
osmosis
- the diffusion of water
- water can have a [] gradient
- water will diffuse down its [] gradient
_____ water has the highest concentration of water and ______ lower the concentration of water
pure, solutes
If you have 2 compartments that are separated by a membrane that is permeable to water but not to glucose, what will happen to the water?
Water moves by osmosis into the more concentrated solution
Pressure that is applied to oppose osmosis is called _____
osmotic pressure
What are the normal physiological concentrations of salts in the extracellular fluid?
K+ = 5 mM Na+ = 145 mM Cl- = 108 mM Ca++ = 1mM
what are the normal physiological concentrations of salts in the intracellular fluid?
K+ = 150mM Na+ = 15mM Cl- = 5mM Ca++ = 0.0001mM
What is the sum of the normal physiological concentrations of salt in the extra and intracellular fluid?
Around 290 mOsM (milliosmoles)
isosmotic
having the same osmotic pressure
hyperosmotic
when extracellular fluid osmolarity is greater than that of the intracellular fluid
hyposmotic
solution with a lesser concentration of solute
why is osmolarity important?
Changing osmolarity of the extracellular solution cause redistribution of water and some solutes in cells
-this causes cells to shrink or swell
The ability of a solution to shrink or swell its cells is its ______
tonicity
If a solution is hypertonic, cells _____
shrink
In a ______ solution, the solution has more solute, water moves down its concentration gradient and cells lose their water
hypertonic
In a ______ solution, extracellular solution has a lower concentration of solute and the water moves down its concentration gradient into the cell
hypotonic
what is the difference between osmolarity and tonicity?
Osmolarity:
- osmolarity describes only the number of solute molecules in a cell
- osmolarity can compare any 2 solutions
- does not tell if a cell swells or shrinks
Tonicity:
- tonicity is a comparative term that describes whether a cell changes volume
- tonicity compares a solution to a cell’s intracellular solution
- specifically tells you if a cell swells or shrinks
_____ depends on the concentration of penetrating and non-penetrating solutes
tonicity
what is a penetrating solute?
- small polar, and non-polar molecules
- ex: urea, glycerol, ethanol
- these can move freely across a membrane
what is a non-penetrating solute
- ions and larger polar molecules
- ex: Na+. Glucose, amino acids
- these cannot move freely across a membrane
if the solute is ______, water will move inside the cell, if the solute is ______, the molecules will move from the higher to lower concentration gradient to reach a balance instead of the water
non-penetrating, penetrating
Hyposmotic solutions are always hypotonic
True or false?
true
intracellular solute are penetrating
True or False?
false
water will flow into the compartment with the highest concentration of ______ solutes
non-penetrating
channel protein
A channel protein is a water filled pore that can open to both sides of the membrane
Ex: water channels, ion channels
-some of these channels are open all the time (open channels) and some are gated channels that open and close with different stimuli (gated channels)
what do channel proteins look like?
The protein will fold and assemble around a central water-filled pore
-they are polytypic (having several variant forms)
what are the 3 types of carrier proteins?
Carrier proteins never form an open channel between the two sides of the membrane
- uniport carriers: only moving material in one direction
- symport carriers: allow more than one type of molecule to cross in one direction
- antiport carriers: allow more than one type of molecule to go both ways
how do carrier proteins work?
- the passage is open on one side (extracellular fluid) and the molecule to be transported enters the protein
- there is a conformational change when the molecule binds to the binding site and the protein closes both sides (transition state)
- there is another conformational change and the passage opens to the other side (inside) of the protein
In terms of energy requirements for carrier proteins, there are 3 categories. These categories are:
1) Facilitated diffusion
2) Primary active transport
3) Secondary active transport
facilitated diffusion
Defined as moving a molecule across a membrane via carrier protein
- does not require ATP - also sometimes called passive transport - cannot accumulate solute against a concentration gradient (chemical equilibrium inside and outside the cell) - ex: glucose transporter (= GLUT proteins)
describe the facilitated diffusion of glucose, what happens to glucose once it enters the cell?
- glucose binds to the transporter
- moves from outside to inside of cell
- sometimes glucose is phosphorylated inside the cell
- it is no longer glucose inside the cell
- glucose can keep moving in by passive transport
- by phosphorylating them, the cell can take more glucose without upping the []
why does a cell phosphorylate glucose
- keeps the [] of glucose low inside the cell
- if the cell actively accumulates glucose, you have lots of molecules inside the cell which ups the osmolarity
primary active transport
- uses ATP
- establishes gradients
- sometimes called pumps
- Na+, K+, ATPase is the most widely known example, but there are others
- Ca++ ATPase
- H+ ATPase
- H+/K+ ATPase
Na+/K+ ATPase
- primary active transport
- pumps 2 K+ ion into the cell, removes 3 Na+ ions
- hydrolyses ATP
- several conformational changes occur
The gradient in the normal physiological concentrations of salts is established by the ______.
-the difference in K+ and Na+ is crucial for many things: ex: it allows the nervous system to generate electrical signals
Na+/K+ ATPase
At rest, the human body produces about ____ watts, the Na+/K+ ATPase in the CNS accounts for ____ watts of that
100, 20
secondary active transport
- active transport
- does not directly utilize ATP as a source of energy
- uses the concentration gradient of one molecule/ion to move another against its gradient
- Na+ -glucose secondary active transporter is a good example
in secondary active transport, what represents the source of energy?
concentration gradient
secondary active transport
1) Na+ binds to carrier protein
a. The intracellular [Na+] is low, [glucose] is high, opposite in extracellular fluid
2) Na+ binding creates a site for glucose
3) Glucose binging changes the carrier conformation
a. Glucose follows Na+ against its [ ] gradient
4) Na+ released into cytosol, glucose follows
Epithelial transport utilizes
- facilitated diffusion - primary active transport - secondary active transport
True or False?
true
describe epithelial transport
1) Na+ K+ ATPase establishes and maintains a Na+ gradient, primary active transport
2) Using the Na+ gradient, glucose is transported into the cell via the Na+ glucose co-transporter, secondary active transport
3) Glucose is transported across the basal membrane by the GLUT transporter, facilitated diffusion
chapter 3 and 4 reading
- pages 166-191
- pages 13-17
what is the importance of cellular signalling?
- economic
- humira = made 16 billion
- advair asthma inhaler = made 4.3 billion
- viagra (1.7 billion) and other ED = 5.1 billion
- cymbalta (1 billion) and SSRIs = 4 billion
- Beta blockers (bloodpressure) = 3 billion
- human
- quality of life
what are the 3 mechanisms for cell-to-cell signalling (local communication)
1) Gap-junction dependent communication
2) Contact dependent signals
3) Paracrine and autocrine
gap junction
1) Channels that connect adjacent cells
a. 2 adjacent cells express channel proteins called connexins
2) Water filled pore: allows small molecules and ions to diffuse from one cell to the next
3) Common in heart, smooth muscle and some neurons
4) Cells are connected by cytoplasmic bridges
___ connexons form a functional gap junction between 2 adjacent cells
-each connexon is made of ___ connexin monomers, this equals to ___ connexin proteins to form one gap junction
2, 6, 12
When cells are connected by gap junctions, they sit together about ___ - ___ nm apart
2, 4
contact dependent signalling
- a molecule (ligand) in the extracellular matrix of one cell binds to a receptor in the membrane of an adjacent cell
- immune system, development
- developing cells need to know who their neighbours are
local communication
- a signaling molecule is released
- paracrine: signaling to cells in the immediate vicinity
- autocrine: signaling to self
long distance communication: endocrine system
- endocrine system:
- secretes hormones:
- chemicals secreted into the blood that affect cells in other parts of the organism
- contacts almost every cell in the body, but only cells with the proper receptors will be affected
- endocrine refers to substance secreted in to blood, such as insulin
- exocrine refers to substances secreted into a duct, such as digestive enzymes from pancreas (into pancreatic duct, then digestive system)
long distance communication: neurotransmitters
- an electrical signal travels distance alone a nerve cell
- causes release of a chemical, the chemical travels across a small gap onto target
- this system is more targeted than the endocrine system
long distance communication: neurohormones (neuroendocrine)
- an electrical signal travels distance along a nerve cell
- causes release of a chemical, the chemical is released into the blood, and acts at distant targets
______ are chemicals secreted by neurons that diffuse across a small gap to the target cell
______ are chemicals released by neurons into the blood for action at distant targets (ex: into the blood stream, cells with proper receptor will be affected)
neurotransmitters, neurohormones
Except for gap junction signaling, cell-to-cell signaling requires what 3 things?
1) Signal (ligand)
2) Receptor
3) Way to transduce the message (intracellular pathways)
The information from secreted signals is converted into what?
intracellular signal pathways or signal transduction pathway
what does a signal transduction pathway do?
- transforms one form of signal to another
- ex: iTunes library information has to be decoded and transferred to something that will process the sound (Broadcom chip) this is then converted into a Bluetooth signal, transformed into a mechanical audio signal (this conversion of the signal is called signal transduction
are signal transduction pathways ubiquitous?
- all cells have some pathways
- only certain cells have specific pathways
why are signal transduction pathways important?
- they amplify signals
- can start with a few ligand molecule and cause a massive reaction in a large number of cells
There are 2 main categories of ligand receptor interaction based on receptor location, what are they?
- intracellular receptors
- cell membrane receptors
intracellular receptor
- ligands are usually lipophilic (hydrophobic)
- steroid hormones for example
- able to diffuse through cell membrane and bind to receptors in the nucleus or cytosol
- often after gene expression (slow but long-lasting)
cell membrane receptors
- &membrane bound organelles
- ligands are usually lipophobic (hydrophilic)
- insulin and other peptide hormones for example
- ligand does not diffuse through cell membrane (but there are exceptions)
- bind to membrane receptors, activates them and causes:
- intracellular cascade
- effects of this in general are quicker and shorter lasting
What are the 4 types of cell membrane receptors?
1) Receptor channel
2) Receptor-enzyme
3) G protein-coupled receptor (GPCR)
4) Integrin receptor
integrin receptor
-binding ligand stimulates changes in cytoskeleton
-cell movement, growth, wound healing
Integrin receptors binds signaling molecules in the matrix of adjacent cells
- changes the shape, and the motility of that cell - important when cells are migrating, can tell cells to keep moving if they are not at their final target yet in the development stages
receptor channels
- multifunctional receptor
- often called
- ligand-gated ion channel
- neurotransmitter gated ion channel
- ionotropic receptors
- the ligand is often a neurotransmitter
- when the ligand binds, the channel opens, allows ions to enter and leave cell (synaptic transmission)
- allow Ca++ into cells (calcium is an important intracellular signal, changes in the [ ] can have important consequences (activation/inactivation of certain proteins)
which cell membrane receptor signal pathway is the fastest?
receptor channels
- this mechanism is fast (within milliseconds)
- going to cause a rapid change in that cell
- fastest out of all the pathways
receptor enzyme and GCPR
- both going to active an intracellular signaling pathway
- real example of amplification
- only takes a few ligand molecules to activate the cell
- amplification of the signal sometimes a million fold inside the cell
-both of these pathways do that because they are linked by an amplifier enzyme
Example of Receptor enzyme: tyrosine kinase receptor
- tyrosine kinase transfers phosphate group from ATP to a tyrosine residue (an amino acid) of a protein (phosphorylates tyrosine residues)
- this phosphorylated protein becomes activated and does other things inside the cell
Specific example of tyrosine kinase receptor: insulin receptor
1) Alpha subunit binds insulin (ligand)
2) Binding of insulin causes receptors to dimerize and autophosphorylate the beta subunit transmits a signal from the bound insulin to the cytoplasm
3) The dimerization and autophosphorylation activates kinase domain in the cytoplasm
4) Kinase domains on the receptor phosphorylate insulin receptor substrate, triggering other responses inside the cell
stages 1, 2, and 3 happen in the extracellular fluid and stage 4 happens in the intracellular matrix
G protein coupled receptor (GPCR)
- hundreds of known GPCR
- many have unknown functions (orphan receptors, many were discovered in the human genome project)
- also called:
- metabotropic receptors
- 7 transmembrane domain receptor (7TR)
- generate second messengers
why are they called G-proteins?
- because they bind to GDP and GTP
- inactive configuration: bind to GDP
- active configuration: exchange GDP for GTP
explain how a g-protein receptor works
- ligand binds to a membrane receptor
- activates signal transduction by G-proteins which activates an amplifier enzyme
- these generate second messenger molecules that can do 1 of 3 things:
- activate protein kinases, phosphorylate proteins
- increase intracellular Ca2+, calcium-binding proteins
- alter ion channels
GPCR example: andenylyl cyclase
1) Ligand binds to G-protein receptor
a. Activates the G-protein
b. 3 subunits (alpha, beta, y)
c. Once activated, the g protein can diffuse along the inside leaf of the membrane (lipid anchored protein)
d. Activated receptor can stimulate several G proteins
2) G protein diffuses along the inside of the membrane to activate amplifier enzyme adenylyl cyclase
a. Each g protein activates on adenylyl cyclase
3) Adenylyl cyclase converts several hundred ATP into cAMP
a. cAMP is the second messenger
b. They can diffuse throughout the cell
4) cAMP activates protein kinase A (PKA)
5) PKA diffuses within the cell to phosphorylate many other proteins
a. Many types of proteins can be phosphorylated, giving rise to complex cellular responses
PL-C
Phospholipase C
DAG
diacylglycerol
PK-C
protein kinase C
IP3
inositol triphosphate
ER
endoplasmic reticulum
GPCR example: phospholipase C
1) Ligand binds to and activates G protein receptor
2) G protein activated the phospholipase C (the amplifier enzyme)
3) PLC degrades membrane phospholipids into 2 2nd messengers: (Diacyglycerol and)Inositol tri-phosphate)
a. DAG stays associated with the lipid (it’s a diglyceride)
b. IP3 is a small polar molecule that diffuses throughout the cytoplasm
4) DAG activates protein kinase C (PKC)
1. PKC diffuses within the cell, and phosphorylates other proteins
5) IP3 binds to the IP3 receptor on the endoplasmic reticulum
1. Activates IP3 receptor, allows store of Ca++ to be released into cytoplasm
2. This Ca++ becomes another second messenger***
what are 4 classic second messengers?
cAMP, cGMP, Ip3, DAG
name 3 novel second messengers
Ca++, gasses, lipids
calcium as a second messenger
1) Binds to the calcium binding protein calmodulin to activate other proteins
2) Binds to motor proteins and allows action of cytoskeleton and motor proteins
3) Binds to synaptic proteins to trigger exocytosis
4) Binds to ion channels to modulate their gating (Ca++ gated ion channels)
5) In fertilized eggs, initiates development
gases as second messengers
- soluble gasses are now being recognized as second messengers
- NO (nitric oxide)
- synthesized by NO-synthase
- NO has half-life of 2-30 seconds
- synthesized by endothelial cells of arteries, and diffuses into adjacent arterial smooth muscle
- activates guanylyl cyclase, production of cGMP leads to relaxation of smooth muscle
- CO (carbon monoxide)
- activated guanylyl cyclase (small amounts are generated within signaling pathways that produces cGMP)
- H2S (hydrogen sulfide)
GPCR example: arachadonic acid
- the arachadonic acid pathway is similar to the PL-C pathway
- g proteins activate phospholipase A2 (amplifier enzyme)
- PLA2 degrades phospholipids into arachadonic acid (an eicosanoid)
- arachadonic acid (and its eicosanoid metabolites)
- are themselves second messengers within a cell
- diffuse out of the cell and act as a ligand for GPCR cell membrane and adjacent cells
For years, physiologists were not able to explain why the hormone epinephrine caused some blood vessels to constrict and others to dilate, we know now that the reason for this is what?
the presence of receptor isoforms, these are linked to different pathways
beta2 receptor dilates, alpha receptor constricts
Some ligands can activate ______ receptors (epinephrine activates alpha and beta2 receptors), while some receptors are ______ (activated by more than one ligand) (alpha and beta2 receptors can be activated by epinephrine or norepinephrine)
multiple, promiscuous
the receptor numbers can be be upragulated or down regulated because of what 3 things?
- development (developing cells have different needs)
- homeostatic challenges
- disease states (sometimes the change in receptor expression might be the cause of the disease, or could be just one of the symptoms)
how can receptors be desensitized?
- phosphorylation of an alpha and beta2 receptor can cause them to have lower affinity for ligands
- mechanism of drug tolerance as a result continuous exposure to an agonist
control pathways: response and feedback loops
-control pathways are generally organized in this kind of manner
- integrating center has to do calculations and make changes
- that signal is carried away (efferent pathway)
- targets tissues and cells
- this generates a response
- this response is intended to generate a signal that will change the amplitude of that stimulus
- feedback loop (what happens between generating this response and the stimulus
negative feedback
- response is meant to decrease the magnitude of the stimulus and shut the loop off
- ex: circulating glucose, insulin becomes secreted and starts taking up glucose that lowers the circulating level of glucose, the response loop will shut off because it brings it back to the initial homeostatic state
positive feedback
- not a lot of examples
- start with a stimulus/response
- response changes some part of your system
- instead of acting to stay at set point, it goes past the set point
- only way it can be shut off is if an outside factor shuts it off
what are the differences between a negative feedback and a positive feedback?
Negative feedback:
- keeps a system near a setpoint
- response acts to negate the stimulus
- response can restore homeostasis, but cannot prevent the initial pertubation
Positive feedback:
- brings a system further from a setpoint
- response acts to reinforce the stimulus
- requires an outside factor to shut off
- non-homeostatic (but many people disagree)
feedforward control
- a small stimulus sets off a chain of events aimed at preventing a pertubation
- ex: fight or flight system
- requires a complex program
- mouth watering in anticipation of food is an often used example
- psychologists may disagree because of the influence of learning
- ex: controlled movement
- mouth watering in anticipation of food is an often used example
Neural signaling is aimed ________, _____ acting, and ______ lived, while endocrine signaling is determined by only receptors, ______ acting, and _______
at a specific target, fast, short
slower, lasts longer
electrochemical gradient
Combination of an electrical gradient and chemical gradient
- ions subjected to an electrochemical gradient will move
- when there’s an electrical and chemical gradient, we consider them as together, not independent
membrane potential of a cell
- is due to electrical gradient across a cell membrane
- unequal distribution of charges (ions)
- established by ATPase transporters
- measured in mV (millivolts)
- not constant
- membrane potential can change due to movement of ions
resting membrane potential (RMP)
- special case of steady-state balance between active transport and leakage ions
- steady state, NOT equilibrium
- for most cells, it’s between -20 mV and -90 mV
In depolarization of the membrane potential, the membrane potential difference ______, in hyperpolarization, the membrane potential difference ______
decreases, increases
In a hypothetical cell, the concentration of K+ is maintained over time. The system is at a steady state where the rate of leakage through leakage channels is exactly balanced by active transport
Is this equilibrium? Why or why not?
no because it requires a constant energy supply
Imagine a hypothetical cell where the K+ pump stops working and no more K+ is going inside the cell. K+ leaks due to the electrochemical gradient
Is this equilibrium?
yes
Imagine a hypothetical cell where the K+ pump stops working. How can we make K+ stay inside if we shut off the pump?
- make the inside negatively charged to attract K+ ions
- we say :”make the inside negative with respect to the outside”
- the amount of voltage necessary to keep the K+ inside is called the equilibrium potential (even though it’s not really an equilibrium)
