Transepithelial Transport

• Transepithelial transport includes transcellular and paracellular transport

Transcellular transport: Glucose transport by intestinal epithelial cells

• Glucose active uptake is mediated by a transporter in the plasma membrane's apical domain, using Na+ cotransport, from the intestinal lumen
• Dietary glucose gets absorbed and concentrated inside the intestinal epithelial cells because of this process
• Glucose transfers to underlying connective tissue and blood supply by facilitated diffusion, mediated by a transporter in the basolateral domain of the plasma membrane
• The Na+-K+ pump, present in the basolateral domain, drives the system
• Glucose uptake from the digestive tract and transfer to circulation relies on the restricted localization of transporters mediating active transport and facilitated diffusion to the respective apical and basolateral domains

Paracellular transport

• Most mucosal surfaces are lined by a single layer of epithelial cells that facilitate transport and serve as a physical barrier against pathogens and toxins
• The paracellular space between adjacent epithelial cells is sealed by a selectively permeable tight junction
• Regulation of tight junction permeability is essential for physiologic and pathologic transport in the intestinal epithelium
• Loss of barrier function has implications in immune-mediated diseases
• Paracellular transport refers to the transfer of substances across an epithelium by passing through the intercellular space between a cell
• Paracellular transport is passive and driven by gradients secondary to transcellular transport mechanisms
• Tight junctions form the major barrier in the paracellular route and vary among epithelia in tightness and ion selectivity
• Regulated back diffusion can modify the molecular composition of transcellular transport
• Some claudins form tight junction-associated pores for paracellular ion transport
• Tight junctions have a net negative charge and preferentially transport positively charged molecules, while also being size-selective and exclude molecules with molecular radii greater than about 4.5 Å
• In kidneys, water transport is accomplished mainly through paracellular transport and transcellular transport, in addition to aquaporins
• In the nephron, paracellular reabsorption of magnesium and calcium occurs
• Intestinal epithelial cells also undergo paracellular transport
• Paracellular magnesium and calcium reabsorption in the nephron depends on the lumen-positive electrical potential that the transcellular reabsorption of other cations and anions establishes
• Na+, K+ and Cl- are reabsorbed through the apical membrane from the tubule's lumen to the cell
• Na+ and Cl- exit the epithelial cell through the Na+/K+-ATPase and the Cl- channel, respectively, at the basolateral membrane
• Na+ backflow through the paracellular channel, occurs because of diminishing luminal Na+ concentrations
• Na+ backflow contributes to the lumen-positive voltage that forces magnesium and calcium reabsorption
• Claudin-16 and claudin-19 facilitate the paracellular transport of magnesium and calcium
• Blood-brain capillaries only undergo transcellular transport, unlike normal capillaries that undergo both transcellular and paracellular transport Hummingbirds and bats depend on paracellular and carrier-mediated intestinal glucose absorption for high fuel metabolism

Ionophores

• An ionophore is a lipid-soluble molecule, typically synthesized by microorganisms, it transports ions across the lipid bilayer of the cell membrane Two classifications of ionophores exist:
• Chemical compounds which are mobile ion carriers bind to a particular ion, shield its charge from the environment, and cross the hydrophobic interior of the membrane, some examples are valinomycin
• Channel formers insert a hydrophilic pore into the membrane allowing ions to pass through while avoiding contact with the membrane’s interior, some examples are gramicidin A.
• Most ionophores from Streptomyces species are polyether antibiotics with a carboxylic acid function
• Ionophores are straight-chain molecules in their uncomplexed form but cyclize with head-to-tail hydrogen bonding in the presence of cations
• An example of an ionophore is Monensin
• Ionophores stacked through the lipid membrane permit Na+ influx
• Ionophores disrupt the membrane potential, are cytotoxic and exhibit antibiotic properties and are produced naturally by a variety of bacteria, many antibiotics have high affinities for Na+ or K+
• In laboratories, ionophores increase the permeability of biological membranes to certain ions, also acting as antibiotics and growth-enhancing feed additives, such as in cattle
• Ionophores are feed additives improve animal body weight gain and feed efficiency in beef cattle diets, altering rumen metabolism to reduce acidosis and bloat

Transmission of information by different cell types

• Biomebranes transmit electric information

Electrochemical gradient

• It is a gradient of electrochemical potential, usually for an ion
• The components of electrochemical gradient include
• -Difference in voltage
• -Difference in ionic concentration

Nernst Equation

• It can calculate the equilibrium potential
• (Veq.) or E defines the equilibrium potential, also known as the membrane potential established at equilibrium, ion is said to be in electrochemical equilibrium
• Nernst equation is used to calculate the equilibrium potential for that ion, if the concentration gradient for a known ion
• If the membrane was only permeable to K+, the membrane electrical potential will equal the equilibrium potential of K+, also known as EK (in volts)
• Em is the equilibrium potential for potassium, measured in volts
• R is the universal gas constant, equal to 8.314 joules. K-1.mol-1
• T is absolute temperature, measured in kelvins (= K = degrees Celsius + 273.15)
• z is the number of elementary charges of the ion in reaction
• F is the Faraday constant, equal to 96,485 coulombs․mol-1 or JV-1․mol-1
• [C]o is extracellular concentration of the ion, measured in m mol-l-1
• [C]i is intracellular concentration of the ion
• Every living cell has a resting membrane potential
• the electrochemical potential corresponds to it, it is a reserve of potential energy that ensures transport of substances necessary for the survival of the cell.
• The electrochemical potential presents in almost all excitable and non excitable cells
• Membrane potential represents the difference in electric charge on the sides membrane
• The main ions that cross the membrane are Na+, K+, Ca2+, and Cl-
• Inside the cell, K+ compensates the negative charges carried by organic molecules and is the predominant positive ion inside the cell
• Animal cell plasma membranes have a greater amount of open K+ leak channels than Na+, Cl- and Ca2+ leak channels
• Neurons at rest are negative in the inside relative to the outside
• Cell membranes allow some ions to pass through channels (ion channels)
• K+ ions easily cross the membrane at rest
• Cl- and Na+ ions are harder to cross the resting membrane
• Establishment of resting membrane potential is the responsibility of three major proteins:
• -K+ leak channel permits K+ diffusion through its concentration gradient
• • Na+ leaking channel permits Na+ diffusion through its concentration gradient
• • Na+/K+ ATPase
• There is no measurable difference in the global concentration of ions across the membrane, although there is an electric potential due to charge separation
• K+ ions are facilitated by concentration gradient can move out of the cell easily, making the inside negative
• Extracellular transfer of charges outwards leaves negative charges unbalanced inside the cell, creating membrane potential and will oppose further movement of K+ towards outside of cell
• Membrane resting potential is almost that of the K+ equilibrium potential
• As a result of Na+ entry through Na+ leak channels, the interior of the cell becomes positive
• Any change in membranes permeability causes a changed of membrane potential
• Na+/K+ pump pumps K+ into the cell and generates the K+ concentration which pulls ions through the leaking channels
• The K+ concentration gradient is not maintained by the Na+/K+ pump, if it is absent or inhibited, resulting in the death of the cell and the drop of the membrane potential
• In living cells, the resting membrane potential is an electrochemical potential and that corresponds to potential energy that maintains the transport of substances
• Nerve cells, muscle cells and some glandular cells are excitable undergo controlled changes in membrane potential
• An action potential will induced by the activation of voltage-gated channels, when exceeding resting membrane potential

Electrical Events

Action Potential (AP):

• Is measured in rapid milliseconds in electrical neurons, with small changes
• The changes are measured in mV
• AP requires electronic amplifiers (1000x) and cathode ray-oscilloscope.
• Intiatation Manifestation: depolarization of the membrane
• -Rate of depolarization increase once there is an initial 15mV depolarization
• -Point of rate change defined as critical firing level, on an oscilloscope reaches and overshoots the isopotential (zero potential) line, the potential is about +35mV, it reverses and falls to resting level
• When repolarization is about 70 % the rate repolarization, decreases the of re polarization, is 70%, tracing approaches resting level more slowly Three voltage-gated channel states are involved in action potential:
• Closed
• Open
• Inactivated
• ’All or None" law states it's possible to find the minimal stimulating intensity current ( threshold intensity ), impulse is produced
• Further increases in strength of stimulus don't change or increment the AP
• The Character AP is "all or none," Nerve impulse can vary in terms of intensity or type and AP doesn't change
• Subthreshold stimuli create an effect even without AP, affects membrane potential, by using millimeters of stimulating electrode
• -The cathode leads to localized voltage change
• -The cathode rises and falls rapidly
• -The anode produces voltage change
• Size and location of electrodes decrease the overall effect
• Cathodal stimulates causes (At –55mV) membrane potential rapidly falls and AP occurs
• Voltage-Gated Na+ channels (Na+CHannel activation) open and rate increases with depolarization is approximately mV7
• At Threshold, rate of potential becomes so inbounding, force overtakes repolarized force
• -If Resting Membrane Potential decreases: Cl- Efflux and K + Influx is restored
• Stimuli Include:
• Electrical
• Chemical
• Mechanical
• Two types Physicochemical Disturbances: in neurons,excitable tissues –Local, nonpropagated potential
• Propagated disturbances: NeurveImpulse/APs
• Response stimulus from -60mV to+30mV is than milleseconds, returns to negative value, change results from rapid sequential Opening/Closing of voltage gated of Na/K, channels

The Action caused by sudden movement of Nat Ions from the cell

• Depolarization
• -The concentration-Gradients of Nats go up
• -At the Internal membrane-Voltage becomes attractive because of Negatively charged ions
• --AFTER proper # Ions are entered Nat channel becomes inactive
• ---Na+ entering Leads the membrane, and causes 30vm increase
• ---Membrane, and membrane, NA Channels enters inactive states until is at initial state.
• ---Repolarization
• The membrane permeability when opened increases because NA+ channels shut off and K starts the action
• ---K+ rushing out of he cell, and causes the re polarization.
• ----K + channels open faster and earlier than the sodium-Pumps with K and sodium is in effect in delayed rate

After Hyper Polarization

K flowing of the cell is driven by membrane-potential K the concentration-Radiant, and cause membrane change from -75 vm The K channels open more than Usual, due to the of Voltage change ( some close when Returns to normal

Additional, K Channel response: Ca 2 causes the K Permability to be unusual

• --Hyper-polarization term There is high/undershoot Transistent term and Permeability will only lower one is at equal value ( potassium. )
• If stimulated again then it can not create a 2nd action potent till its return to previous form and can become stable ( The membrane is now deemed now is not the time.
• After the previous stimulus, if the cells is stimulated it cannot produce 2nd until its in natural form or position. During this state the membrane, is referred to as Stimuli- Resistant/Refractory. Phase.
• Neurons channels are inactive due to its period/ phase one is not at its action site for the next trigger can open properly or function transport will not work

Role of the refractory period

• Refracting-period: Is the limitations of time, the channels activate or allow for neuronal- signaling
• Additionally refracting - Period, helps facilitate AP along the Atom