What should a pharmacist care about membranes?
Barrier for drug absorption and excretion and getting into brain Hold proteins and are critical for electrical signaling
What are the two classes organisms and what are they based off of?
Based off cell structure 1. Prokaryotes: no nuclear compartment 2. Eukaryotes: has nucleus
What are some characteristics of prokaryotes?
1. no nuclear membrane (no nucleus) 2. No membrane bound organelles 3. Has a cell wall 4. circular chromosome EX: e coli, staph and strep
What are some characteristics of eukaryotes?
1. Nuclear membrane surrounding genetic material (nucleus) 2. Numerous membrane bound organelles 3. Complex internal structure with cytoskeleton 4. much larger EX: Homo sapiens, Oryza sativa
What is the cytoplasm in the eukaryotic cell?
Everything inside the cell expect the nucleus
What is the cytosol within the eurkayotic cell?
The fluid portion of the cytoplasm (organelles). site of glycoloysis
What is the nuclear envelope of the eurkayotic cell?
Segregates chromatin (DNA + Protein) from cytoplasm
What is the plasma membrane of the eurkayotic cell?
Separates cell from environment, regulates movement of materials into and out of the cell
What are the ribosomes of the eukaryotic cell
What are the peroxisomes of the eukaryotic cell?
Degrade lipids using peroxides
What is the cytoskeleton of the eukaryotic cell?
Supports cell, aids in movement of organelles and cell (cilia and flagella)
What are the lysosomes of the eukaryotic cell?
Degrade intracellular debris
What are transport vesicle of the eukaryotic cell?
Shuttles lipids and proteins between ER, Glogi, and plasma membrane
What is the golgi of eukaryotic cell?
Process, packages, and targets proteins to other organelles or for export
What is the smooth endoplasmic reticulum (SER) of the eukaryotic cell?
Site of lipid, steroid, and triaclyglycerol synthesis. drug metabolism by CP450s happen here
What is the nucleus of the eukaryotic cell?
Contains the genes (chromatin) and is where DNA and RNA synthesis occurs
What is the nucleolus of the eukaryotic cell?
Site of ribosomal RNA synthesis
What is the rough endoplasmic reticulum (RER) of the eukaryotic cell?
Site of much of the protein synthesis
What is the mitochondrion of the eukaryotic cell?
oxidizes (oxidative phophorylation) to produce ATP. Has own DNA, site of citric acid cycle
What is the bacterial cell wall?
1. Present in almost all prokaryotes 2. Composed primarily peptidoglycan 3. the cell wall forms a "mesh" around the cell providing structure
What type of peptidoglcan are most type of cell walls composed of?
What is peptidoglycan?
Complex construct of carbohydrates and amino acids
What is the cell wall of a gram positive bacteria?
1. no outer membrane 2. much thicker peptidoglycan layer
What is the cell wall of a gram negative bacteria
1. Outer membrane present 2. Much thinner peptidoglycan layer
What is the function of the bacterial cell wall?
1. Maintains cell shape/integrity 2. Prevents lysis from extreme environmental conditions
What is the Structure of the bacterial cell wall?
1. Backbone composed of carbohydrate polyermers 2. Backbone strands are crosslinked together by short peptide chains -- unusual amino acids such as D-alanine and DAP 3. These result in structure that is rigid, yet flexible and porous "net" around the bacteria
What are the stages of Bacterial cell wall synthesis?
1. Peptidoglycan dimer is synthesized inside cell wall 2. movement of dimer to the outside of the cell membrane 3. Peptidoglycan polymer synthesis 4. crosslinking by the enzyme transpeptidase
What is job of B-lactam antibiotics?
They inhibit (block) transpeptidase enzymes so crosslinking cant occur
What are some examples of B-lactams ?
1. penicillins - Amox, Penicillin V 2. Cephalosporins - Cephalexin 3. Monobactams 4. Carbapenems
How does the inhibition of Transpeptidase by penicillin work?
The pocket of the bacteria that needs to be linked together by the side groups of penicillin such that hydrolysis by water cant happen. This makes transpeptidase being irreversibly inhibited, leading to no crosslinking to cell death
What does a bacteria do to have drug resistance?
The bacteria produces production of a B-lactamase enzyme which chemically degrades (destroys) the B-lactam drug
What are ways we have overcome the bacterial drug resistance ?
We targeted the B-lactamase enzyme Augmentin is a combo of B-lactam antibiotic and clavulanic acid -- The clavulanic acids acts as an irreversible inhibitor of B-lactamase to prevent the cleavage and inactivation of the amoxicillin
What are the composition and architecture of membranes
1. Composition of membranes varies between different membranes 2. Membranes form compartments (specialized environments) which are necessary for nearly all bio processes 3. Provide structural framework on which many enzymatic reactions occur 4. Membranes serve as a reservoir for a variety of signaling molecules allowing cell to receive external stimuli
What is the membrane composition of lipid membranes?
1. Glycerophospholipids - most abundant 2. sphingolipids 3. cholesterol
What is the membrane of composition of protein membranes
1. Peripheral 2. integral
What is the membrane composition of carbohydrate membranes?
*always attached to lipid or protein membrane 1. Glycolipids 2. glycoproteins
What are the two main components of lipid membranes?
Polar head group - hydrophilic Long nonpolar tails - hydrophobic
What does it mean if a membrane has an amphipathic nature of a membrane lipid?
The polar- nonpolar duality of the membrane. This is important because it allows them to form biological membranes
What is the amphipathic association in an aqueous environment?
Amphipathic molecules tend to associate non-covalently with on another - polar heads associate with water - non-polar tails associate with on another
How does amphipathic association lead to closed membranes?
Its energetically unfavorable to have hydrophobic tails surrounded by water, so there are lipid layers form closed structures
What is micelles?
Closed membranes Small spherical balls of lipids with only one polar surface and a hydrophobic core
What are liposomes?
Closed membranes Artificially-made vessicles with a hydrophilic core that are sometimes used for drug delivery - hydrophilic core
What are bilayers?
Closed membranes Two layers of lipids with the lipid tails in the middle of two polar layers formed by the polar head groups
What is the structure of a lipid bilayer?
Two sheets of lipids with on layer of polar head groups facing the aqueous exterior of the cell or vesicle with the other polar surface faces the aqueous interior. The nonpolar tails "sandwiched" in between ***Impermeable to almost all polar or charged solutes, permeable to most nonpolar compounds
Do the sheets of membranes need to be the same?
No, most studies that the inner and outer leaflets (polar hydrophillic ends) are different, asymmetric
What are fatty acids?
Simplest form of lipid Contains two components - carboxylic acid -Long non-polar tail - can be saturated with no double bonds or unsaturated with one or more double bonds to make kinks
What are the types of lipids?
Triaclycerols, storage form for lipids Phospholipids - glycerophospholipids account for 40-60% of content in bio membranes Glycolipids (carbohydrates attached) Steroids (cholesterol)
What is important about triacylglycerol?
1. Have glcyerol backbone, three fatty acids and no phosphate 2. named triglycerides 3. Most abundant class of lipids in the body 4. NOT significant component of cell membranes 5. Function is primarily as energy reservoirs for the cell
What is important about phopholipids?
1. can be either glycerophospholipids or sphingophospholipds 2. have three main components - One or two fatty acids - Backbone (glycerol) or sphingosine 3. Phosphate molecule with an optional polar head group attached
What is important about glycerophospholipids
1. Have three main components - glycerol backbone - two fatty acids - phosphate group with optional polar head group 2. Account for 40-60% of content in bio membrane 3. The FA group provide diversity because they can be either saturated or unsaturated
What is the simplest glycerophospholipid?
What is important about sphingolipids?
1. Three main components - Sphingosine backbone - One FA linked as an amide to sphingosine - Polar head group (with or without phosphate) 2. Account for 10-20% of bio membranes 3. very common in myelin sheath 4. if you attach a saccharide group (sugar) it becomes glycosphingolipids
Whats the simplest sphingolipid?
Whats important about Cholesterol?
1. Important component of bio membranes and is the most abundant steroid in animals -30-40% of bio membranes 2. Only slightly amphipathic and is rigid, not hydrophilic enough to form a bilayer 3. Its presence in a membrane increases the membranes overall rigidity
What are the two nonlipid protein components of membranes?
-Peripheral membrane proteins - Integral membrane proteins
What are Peripheral membrane proteins?
Proteins which are only temporarily associated with the membrane - Held there by electrostatics or hydrogen binding -can have lipid anchors (b-subunits, G-proteins)
What are integral membrane proteins?
Proteins which are integrated with (extend into or through) the membrane - FIRMLY associated with the membrane - function as cellular receptors or may transport substances into or out of the cell
What is the structure of integral membrane protein?
1. Have sections (domains) that pass through the hydrophobic section of the lipid bilayer 2. These trans-membrane domains generally have hydrophobic amino acids, usually contained in an alpha helix 3. Proteins will have multiple domains that span the membrane
What is the fluid mosaic model of membranes?
1. the membrane has shape, but is not rigid 2. The membrane is fluid-like with a "mosaic" of proteins embedded in or attached to the phospholipids 3. This lack of rigidity allows for the lateral diffusion of lipids and proteins in the membrane and conformational changes of membrane proteins
What is membrane Fusion?
Its when adjacent membranes can fuse together to form a single membrane - this is almost always assisted by proteins (i.e. SNARE proteins)
What is meant by membranes being semipermable?
A membranes primary function is to separate two areas. - this lipophilic layer of membranes makes them semipermeable, certain things can go thro it.
What is able to get thro a semipermeable membrane?
1. small, nonpolar molecules can cross 2. Small, polar, uncharged molecules have some ability 3. Larger molecules, or charged, polar molecules have very low permeability
What are the two transport mechanisms?
1. passive transport 2. active transport
What is meant by passive transport?
1. Requires no energy 2. Moves with a gradient (high to low) 3. May require proteins for assistance (channels or pores) 4. Transport stops when concentrations are equal across membrane
What is meant by active transport?
1. requires energy 2. molecules move against the gradient (low to high) 3. requires proteins for assistance (transporters or pumps) 4. goes beyond equilibrium
What are the two types of passive transport?
1. simple diffusion 2. facilitated transport or facilitated diffusion
What is simple diffusion?
Passive transport 1. Hydrophobic compounds 2. Small, nonpolar molecules 3. Small, polar, uncharged molecules
What is facilitated transport or facilitated diffusion?
Passive diffusion 1. Hydrophilic compounds cannot cross lipid bilayers by simple diffusion 2. Require a membrane protein to transport them across 3. protein forms a channel or pore thro the membrane so molecule can pass thro without using energy
What is the equilibrium process?
Its the passive diffusion of molecules across a membrane
What is the concentration gradient?
1. has solute concentration (Na+ or K+ ions) 2. solvent concentration or osmotic pressure
What does C1 represent?
The concentration where the solute is moving from (outside concentration; extracellular)
What does C2 represent?
The concentration of the solute where it is moving to (inside concentration; intracellular)
What is the electrochemical gradient?
1. for ions, is a combo of the concentration gradient and the electrostatic potential across the membrane 2. often used in the mitochondria in the form of proton motive force for production of ATP
What is fick's law of diffusion?
Describes the passive flux (rate of diffusion) of a solute down a concentration gradient
How does the size of molecules relate to their diffusion?
Its inversely proportional to its diffusion coefficient - means the larger the size, the slower the diffusion
How does a molecules lipophilicity or hydrophbiity affect its diffusion?
Generally, the more lipophilic, the faster the diffusion but its more complex than that. - the arrangement of the molecule has a lot to do with it as well as the environment. ** better to think of it as a balance of hydrophobic and hydrophobic groups have a higher rate of diffusion.
What is osmosis?
The tendency of solvent (i.e. water) to move across a semipermeable membrane from an area with high solvent concentration to an area with low solvent concentration
What happens to water in an isotonic environment?
The amount of water is the same on the inside as it is on the outside of the cell
What happens to water in a hypotonic environment?
Less amount of solvent inside the cell so water enters the cell and causes the cell to burst
What happens to water in a hypertonic environment?
Solvent concentraion is lower on the outside of the cell which makes water LEAVE the cell causing it to shrink and die
What is the clinical important of osmosis?
Deals with the reabsorption of water ( and concentration of urine) in the kidney leading to fluid exchange in capillaries EX: you get more Na+ in your system that leads to the kidney to reabsorb more water which will increase your blood pressure
What do proteins do with activation energy?
The cost to move polar/charged solutes across the lipid bilayer is large - Membrane proteins lower the activation energy for the transport of polar/charged solutes
What are channels or pores in facilitated transport?
1. lower specificity than carriers and usually oligomeric proteins 2. Vary fast rates of transport 3. direct link between inside/outside of cell 4. Not saturable
What are carriers in facilitated transport?
1. Higher specificity than channels and monomeric 2. Transport rates faster than simple diffusion 3. NOT a direct link between inside/outside of the cell 4. Saturable
What is primary active transport?
1. uses energy directly from ATP 2. Will bind ATP and hydrolyze it
What is secondary active transport?
1. Uses energy indirectly from ATP 2. Coupled with primary transport system that directly uses energy to make a gradient to drive the secondary active transport system
What are uniporters?
Transport one type of molecule
What are symporters?
Transport different molecules in the same direction
What are antiporters?
Transport different molecules in the opposite direction (one in, one out)
how does glucose Transporters: GLUT1 work?
1. glucose binds to transporter (T1) 2. Transporter undergoes conformation change to T2 3. glucose then enters the cell 4. Transporter returns to T1 conformation *inside the cell it is turned into gylcogen
How do glucose transporters: GLUT4 work?
1. Glucose transporters "stored" within the cell 2. When insulin interacts with its receptor, vesicles move to the surface and fuse with the plasma membrane, this increases the number of glucose transporters in the plasma membrane 3. When insulin level drops; the transporters are removed from the plasma membrane 4. the smaller vesicles fuse with larger endosomes
What type of diffusion is used by ion channels?
Examples of facilitated diffusion - are NOT ion pumps and they dont require energy
What are the two types of ion channels?
Voltage-gated ex: Na+ channel Ligand-gated EX: nicotinic acetylcholione receptor
What are example of primary active transport?
The sodium potassium pump found in a variety of tissues (nerves, muscle) ** its primary because the protein DIRECTLY uses ATP for energy
What does the Na+/ K+ ATPase do?
Creates higher Na+ concentration outside the cell and higher K+ concentration inside the cell * Pumps 3 Na+ out and 2 K+ ions in every time it operates *this creates electrical gradient in addition to chemical gradient
What is an example of secondary active transport?
Sodium glucose cotransporters (SGLTs) They use higher concentration of Na+ outside the cell, produced by sodium pumps, to bring glucose inside the cell *SGLTs are symporters because they bring both glucose and sodium into the cell *It can pump glucose into the cell to around 9000 times the concentration outside
How are neurotransmitters as secondary active transport
1. They transport from an area of low concentration (synapse) to an area of high concentration (cytoplasm) and it requires energy 2. They DO NOT use ATP directly as an energy source - this is provided by the Na+/K+ ATPase pump which forms a concentration gradient 3. They are symporters and bring either Na+ or Cl- in with the neurotransmitter
What are the types of mechanisms in cell-to-cell communication?
1. Chemical communication: release of a chemical or protein from one cell that affects another 2. electrical communication: proagation of electrical signals (action potential)
What type of communication is an Autocrine?
It communicates directly with itself -Secreting cells receptors on their cell surface receptors that recognize the signaling molecule they secrete
What is juxtacrine?
Signaling cell must touch the target cell
What are contact-dependent signals?
Juxtacrine Membrane-bound molecules on one cell bind to a molecule on another cell membrane EX: Notch signaling in neural development, wound healing
What are gap junctions?
Juxtacrine Direct cytoplasmic transfer of electrical and chemical signals between adjacent cells EX: heart contractions, embryonic tissue development
What are paracrines?
A molecule is released by signaling cell diffuses to neighboring target cells of a different cell type EX: neurotransmitters
What is endocrine type of cellular communication?
Between distant cells Molecule (hormone) secreted by signaling cell is transported to the target cell via the bloodstream EX: Oxytocin, insulin, androgens
What is cellular excitability?
Ability of a cell to generate and propagate action potentials
What is voltage on an electrochemical basis?
The measure of the potential energy caused by a difference in charge between two points
What is the resting potential?
The voltage across a membrane, the difference between intracellular and extracellular potentials
The basis for the resting potential depends on what three things?
1. membrane maintains charge separation between extracellular and intrcellular ions 2. ion pumps move ions across the membrane and establish gradients 3. ion channels allow passage of ions
What determines the direction of a charged solute moves across a membrane?
Depends on both the chemical gradient and the electrical gradient
What is the resting potential for most cells?
Vm = -70 mV
What does depolarized mean?
When the Vm is more postive than the resting Vm
What does hyperpolarized mean?
When the Vm is more negative than the resting Vm
What are the four major types of ion channels?
1. Na+ channels 2. K+ channels 3. Ca2+ channels 4. Cl- channels
What causes changes to the permeability of membranes to ions ?
The opening and closing of ion channels does this * Increased Na+ permeability DEPOLARIZES the membrane * Increased K+ permeability HYPER-POLARIZES the membrane
What is a mechanically-gated ion channels
a sensory neuron responds to physical forces (stretch or pressure)
What are ligand-gated ion channels?
Respond to various ligands binding to the channel (neurotransmitters)
What are voltage-gated ion channels?
Respond to changes in the membrane potential
How does Na+/K+ ATPase pump maintain resting gradients?
1. pumps 3 Na+ ions out and 2 K+ ions in every time it operates 2. Creates electrical gradient in addition to chemical gradient 3. uses ATP to pump ions
What is happening to the Na+ and K+ channels during resting potential?
Both channels are closed
What happens to the channels when the threshold is reached
Both Na+ channels open (Na+ enters the cell) and this leads to depolarization
What happens to the channels during repolarizations?
The Na+ channels close and the the K+ channels opens causing K+ to leave the cell
What happens to the channels during hyperpolarization?
Both Na+ and K+ channels are closed and which allows the cell to return to its resting potential
What is the absolute refractory period?
Is the time from the start of the action potential until the cell turns to the resting potential - No stimulus can trigger another action potential - Na+ channels have to reset
What is the relative refractory period?
Is the time after the cell reaches the resting potential, hyperpolarizes, and then returns to the resting potential - A larger than normal stimulus can trigger another action potential
What is synaptic transmission?
The communication from a nerve to another cell (nerve or muscle) when an action potential reaches the end of the nerve cell
What is the synapse?
A junction where communication occurs; small gab between the two cell
What does the presynaptic neuron synthesize?
Messenger molecules called neurotransmitters which carry the signal to the next cell
Where are neurotransmitters stored?
In vesicles within the presynaptic neuron until a signal is received and then they are released
What are the steps in synaptic transmission?
1. Neurotransmitters are synthesized and packaged inside vesicles at the end of pre-synaptic cell 2. An action potential travels down the neuron and depolarizes the terminal end of the presynaptic neuron 3. Depolarization activates voltage-dependent Ca2+ channels resulting in Ca2+ influx into the cell 4. The inc in Ca2+ enables vesicle fusion with the membrane and release of neurotransmitter into synaptic cleft 5. The neurotransmitter diffuses across the synaptic cleft and binds to a postsynaptic receptor -ligand gated = depolarization of postsynaptic cell -GPCR = intracellular signaling cascades 6. The signal is removed from the synapse thro the removal of the neurotransmitter from the synaptic cleft - neurotransmitter can be degraded by enzymes in the synaptic cleft -neurotransmitter can be recycled back into the presynaptic cell by re-uptake 7. Intracellular signals are terminated by enzymes (such as PDEs) that degrade signaling molecules (such as cAMP)
What is the name of the boundary between the nerve and muscle called?
What happens in action potential propagation at the neuromuscular junction?
1. The AP at the last nerve cell triggers release of acetylcholine into the neuromuscular junction 2. When ACh binds, the channels opens and allows Na+ into the skeletal muscle cell
What are the steps of Transmission at the neuromuscular junction?
1. AP in neuron is propagated to the end of the neuron 2. AP triggers the opening of voltage-gated Ca+ and Ca+ enters 3. The presence of Ca+ triggers fusion of synaptic vesicles containing ACh and releases it 4. ACh diffuses across the space between the nerve and muscle cell and binds to receptor sites on the muscle cell, opening channels, leading to Na+ entering the cell and K+ leaving the cell 5. results in an action potential 6. The action potential is propagated through the muscle fiber 7. ACh either diffuses away or is destroyed by acetylcholinesterase
What is the big difference between AP in cardiac muscle and skeletal muscle?
When the sodium channels close, voltage-gated calcium channels open as well as the K+ channels
What is different about Ca+ channels?
They are "slow" to open and close
What does "slow" Ca+ channels do in terms of how it affects AP of cardiac muscle?
Because the Ca channels stay open longer the balance between the Ca2+ inflow and the K+ outflow, there is a plateau in the re-polarization phase called the calcium plateau
Why does cardiac muscle have a longer absolute refractory period?
1. the calcium plateau is caused by the opposing flow of potassium and calcium which balances the charges 2. This leads to no change in the polarization of the cell - Pos K+ leaves the cell - Pos Ca+ enters the cell -this means there is no net change in charge across the cell membrane until the calcium channels close
What does overstimulation of action potentials lead to in each type of cell?
Nerves = seizures and disruption of signal conduction Cardiac muscle = lead to arrhythmia in the heart Skeletal muscle = tetanus of skeletal muscle cells
What is the process of depolarization of nerve cells?
1. When the nerve cell receives a stimulus, the cell membrane is depolarized 2. Depolarization occurs when some of the voltage-gated sodium channels open, allowing sodium to enter the cell 3. As Na+ enters, the interior of the cell becomes more positive until it reaches a threshold potential of around -50 to -55 mV 4. Once this threshold is reached all the voltage-gated Na channels open, allowing an even more rapid influx of Na.
How does repolarization of nerve cells work?
1. influx of Na will continue until the volate reaches +35-50 mV, at which time the voltage-gated sodium channels close 2. Then the voltage-gated K+ channels open allowing potassium to rush out of the cell 3. as K+ leaves the cell the interior of the cell becomes more negative again