Physiologic Control & Membrane Transport Flashcards
Allostasis
A stress specific term that refers to the ability to maintain homeostasis in the face of chronic challenge. Allostasis
comprises the adaptive responses to chronic stress that may include establishment of a new set point. Allostasis is important in the concept of compensation for failing systems: compensated heart failure, compensated renal failure, compensated liver failure, etc.
Compensation vs. Decompensation
Compensation - ability to maintain a stable state (though not necessarily normal state) during time of organ injury or failure (i.e. compensate heart failure)
Decompensation - the inabililty to maintain a stable state following organ injury or failure
Core Body Temp. Regulation
Closed negative feedback loop
Overal regulation sensed and localized to hypothalamus or spinal cord
Set point
This is aspect of a homeostatic control system can be reset - raised or lowered.
Agreement of body systems with this intended value is achieved by balancing inputs (+) and outputs (-). There can be several competing control systems with cumulative (agonistic/antagonistic) effect
If temperature sensors sense cold temp
They send reduced signal to the hypothalamus, which in turn, sends a mesage to skeletal muscle to initiate shivering and brown adipose to burn fuel
Endogenous pyrogens
Cytokines such as some interluekins and tumor necrosis factor
Endogenous pyrogens increase prostaglandin E2 (PGE2) production in the hypothalamus
PGE2
resets the temperature set point to a higher value
Subsequently, the hypothalamus activates heat generating and heat storage pathways (shivering/reduced cutaneous blood flow, respectively) to raise core temp.
Error signal
Set point - signal from temperature sensors
Neg error - tells body to activate mechanism (sweating redirecting warm blood from core to skinn) to min. core temp elevation
Pos error - body is instructed to activate mechanisms to raise core temp
Blood glucose regulation
Negative feedback - becuase insulin and enhanced glucose uptake reduce the error signal and drive plasma glucose back toward the set point
Negative feedback loops - controlled variable adjusts regulated variable back in the opposite direction
Homeostasis
Necessitates a control or regulatory system that can sense deviation form normal (set point) and initiate corrective responses to return the system to normal balance.
Local - cellular homeostasis
Regulated variable - variable with a set point
Controlled variable - variable that is part of the corrective response
Difference between equilibrium and steady state (dynamic equilibrium)
Dynamic equilibrium - energy must be consumed
Negative feedback examples
Core body temp
BP
Fluid/electrolyte balance
Plasma glucose levels
Negative feedback = the controlled variable pushes the regulated variable in the opposite direction back to the set point
Componenets of a homeostatic reflex
Difference in temperature regulation of exercise and fever?
In exercise, the temperature set point does not change as core temperature rises. The error signal is the set point minus the signal from temperature sensors. The negative error tells the body to activate mechanism (sweating, redirecting warm blood rom core to skin) to minimize core mperature elevation.
In fever, the set point is increased, and temperature sensors now report a low core temperature. The error signal (set point minus actual core temperature) is positive and the body is instructed to activate mechanisms to raise core temperature to the new set point (shivering, reducing cutaneous blood flow, etc.).
Three main factors of diffusion across cell membrane
Concentration gradient
Channel conductance
Number of open channels
Membrane Conductance = #Channels open x Channel conductance
Pores
Always open, but generally few in number and have a low channel conductance
Gated channels
Pores with a cover - allows the membranes to regulate the pores (open and closed)
Often have high conductance (readily let the substrate flow)
Large in number, but are almost always closed
Protein Carriers
Used to shuttle large molecules
Becuase it is possible to saturate carriers - the number of carriers is most important in determining the rate at which the molecules of a given substance can move across the membrane
Active Transport
Move molecules up its concentration gradient (against the diffusion equation)
Primary active transport - ATP hydrolization
Secondary active transport - harnessing energy of another substrate’s concentration gradient
Cotransporters/uniporters
The Na+-glucose cotransporter (SGLT 1)
Na+-K+-2Cl- (renal tubules) is response for regulating ions using the concentration gradient of sodium to bring one potassium and two chloride ions against their gradient into the cell
Secondary active transport
Antiporters
Na+/Ca2+ antiporter - utilizes the energy of sodium coming down its concentration gradient (3 Na+ in), to push calcium up its concentration gradient (1 Ca2+ out)
Na+-H+ antiporter: 1 Na+ in, 1 H+ out
What molecules can diffuse acrosse the lipid bilayer?
Small w/ and/or lipophilic
Gases: O2, CO2, NO
Water, urea, EtOH, and steroid hormones
Relationship between diffusion distance and time for diffusion
Diffusion is a slow process (figure to the left). The time for diffusion increases with the square of the diffusion distance.
(∆x)2 = 2Dt
GLUT 1
Km = 3-7
Ubiquitous distribution in tissues and cultured cells
Fx: basal glucose uptake: transport across blood tissue barriers
GLUT 2
Km = 17
Liver, islets, kidney, small intestines
Fx: High-capacity, low-affinity transport
GLUT 3
Km = 1.4
Brain and nerve cells
Fx: Neuronal transport
GLUT 4
Km = 6.6
Muscle, adipose, heart
Fx: Insulin-regulated transport in muscle and adipose
GLUT 5
Intestine, kidney, and testis
Transport of fructose
P-Type ATPases or pumps
Transporting protein is phosphorylated during the catalytic cycle
Na/K ATPase
Ca ATPase
proton or H/K ATPase
The Na/K ATPase consumes the greatest fraction of cellular energy
V-type ATPase pump
Vacuolar or lysosomal proton pumping ATPases acidify intracellular organelles
F-type ATPase or pump
Mitochondrial F1F0 ATPase - ATP synthase
ABC Transporters
Transport lipids, hydrophobic drugs, other substances - located in the plasma membrane
Aka multi-drug resistance (MDR) pumps becuase of their enhanced expression and function in cancer cells resistant to many chemotherapy drugs
Essential for hepatic transport of organic acids and bile salts into bile
Short-Term Regulation of Na/K ATPase
Short-term regulation:
1. Km for intracellular Na = 15 mM and [Na] = 10 mM
2. Km for extracellular K is 0.5 mM and extracellular [K] = 4 mM (Extracellular potassium is almost never rate-limiting for pump activity)
3. Sodium pump activity is acutely influenced by hormones that raise intracellular cAMP and increase tyrosine phosphorylation of the alpha-subunit (norepinephrine and dopamine)
4. Insulin can cause insertion of pump units into the plasma membrane and activation by phosphorylation. Dopamine can cause tissue-specific insertion or retrieval of pump subunits at the membrane
Long-Term Regulation of Na/K ATPase
- Hormones: insulin, thyroxine, mineralcorticoids (aldosterone) - activate expression of sodium pump genes in many tissues including skeletal muscle and kidney
- Prolonged elevation of intracellular sodium activates pump gene expression
Na-glucose co-transporter
Na-Ca Exchanger (NCX)
Secondary active transport
Na-H Exchanger (NHE)
Secondary active transport
Na/K/Cl Cotransporter (NKCC)
Secondary active transport
Secondary active transport for epithelial absorption of glucose
Analagous to transport of AA’s across epithelial cells (different transporters)
Difference between channels and pores
Channels are gated
Pores are not (always open)
Fick’s first law of diffusion
The diffusion flow (flux) is proportional (diffusion constant) to the concentration gradient (force)
Ji = -DiA ∆Ci/∆x (Units for Ji are mmol/sec, units for Di are cm2/sec)
or
Jv = Kf ∆π
Where Jv is the volume flux (ml/min)
Kf is the hydraulic conductivity of the membrane (ml/min-atm)
∆π is the difference in osmotic pressure across the membrane (atm)
Van’t Hoff Law
𝜋 = 𝑅𝑇(i𝐶)
Works well fo dilute solutions not concentrated ones (becuase dissolution is no longer 100%)
For concentrated solutions, An osmotic coefficient (ɸ) constant is added to account for this nonlinearity. Now van’t Hoff’s Law becomes:
𝜋 = 𝑅𝑇(ɸ)(i𝐶)
Osmolarity vs. Tonicity
Tonicity = osmolarity x reflection coefficient
Hdryostatic and Oncotic force
Nernst Equilibrium Equation
Defines the electrical equilbrium potential (voltage) across a membrane due to the unequal distribution (concentration gradient) of permeant ion.
Takes the base-ten log of the concentration of ion C outside of cell over concentration of ion C inside of cell
Which direction ions move (in or out of the cell)
The Na/K ATPase and Membrane Potential
The importance of the Na/K ATPase to establishing and maintaining the membrane potential of every cell of the
body can’t be overstated.
Poisoning or inhibiting the Na/K ATPase (with ouabain or its analogues) or blocking ATP production leads to
collapse of the Na and K gradients (Na accumulates in cells and cells loss of K), depolarization of the membrane
toward zero mV, and swelling of cells (as they accumulate Na and water).
Voltage-gated Na+ channels
Exhibit positive feedback. When a depolarizing stimulus reaches threshhold, channels begin to open. This increases membrane permeability (conductance) for Na driving membrane potential toward the Na equilibrium potential (near +50 mV). As the membrane depolarizes, additional Na channels open in a positive feedback cycle. Na channels open briefly before closing (inactivation), limitng the length of the action potential depolarization.
Voltage-gated K+ Channels
K+ channels exhibit negative feedback.
They also open by depolarization, but more slowly. As depolarization reach peak positive values, K channels open as Na channels close. The membrane permeability shifts from Na dominant back to K dominant and membrane portential moves back toward the K equilibrium poteneital (-90 mV). As the membrane repolarizes to more negative values, K channels close in a negative feedback cycle.
Action Potential
Diagram w/ labels
Absolute vs. relative refractory period
Absolute = when the inactivation gates of Na channels are shut, and the channel has not recycled back to an openable configuration
Relative = when the Na channels have been reset but the still open K channels and hyperpolarized membrane require a greater stimulation than normal to get the membrane to threshold
Basic structure of voltage-gated channel subunit
Voltage sensor
The fourth alpha helix (S4) contains charged AA’s arranged so that the helix can move up or down in the membrane in response to changes in membrane voltage - this segment is the voltage sensor
Interacts with the pore domain to open the activation gate
The pore domain
Contains a P loops that forms part of the channel. The four P loops, one from each subunit, come together to form the actdual pore.
The AA’s of the P loop determine the ion specificity of that pore (i.e. the P loops of Na channels have different configuration than P loops of K channels)
Tetrodotoxin (TTX)
Puffer fish toxin that blocks fast voltage-gated Na channels (causing paralysis and death)
Tetra ethyl ammonium (TEA)
Voltage-gated potassium channel blocker
Knee jerk
The sensory neuron is activated by stretching the thigh muscle and in turn activates motor neurons in the spinal cord. Activity in the motor neuron causes contraction of the thigh muscle. The stretch receptor sensory neuron of the quadriceps muscle makes an excitatory connection with the extensor motor neuron of the same muscle and an inhibitory interneuron projector to flexor motor neurons supplying the antagonisitic hamstring muscle
Synapses
Types - diagram
A) May be ligand-gated channel receptors or the receptor closely associates with a channel. Alternatively, some receptors are G-protein coupled membrane proteins
B) The result of direct connections between cells by gap junctions that allow membrane voltage to flow from one cell to another
Steps in process of transmission at chemical synapses
Presynaptic action potential and acetylcholine release
Nicotinic acetylcholine receptor
The receptor at the neuromuscular synapse (motor neuron to skeletal muscle) and many nerve-to-nerve synapses in the spinal cord and other parts of the CNS
Upons binding an Ach to each alpha subunit, the channel opens and conducts Na and K equally.
The large increase in Na conductance results in a steep depolarization
What toxin(s) inhibit ACh release?
Tetanus toxin
Botulinum toxin
What toxin(s) inhibits K+ channels?
Dendrotoxin
What toxin(s) inhibit acetylcholinesterase?
Physostigmine
Diisopropyl flourophosphate (DFP)
What toxin(s) inhibit the muscular Na+ channels?
Tetrodotoxin
Saxitoxin
μ-conotoxin
Tetrodotoxin and saxitoxin both inhibit neuronal Na+ channels as well
What toxin(s) inhibit the AChR channel?
d-Tubocararine
α-bungarotoxin
Toxins from a frog and snake respectively that are antagonist for the ACh receptor and block synaptic transmission
What toxin(s) inhibit voltage-gated Ca2+ channels?
ω−conotoxin
Toxin from snail and blocks the synaptic voltage gated Ca channel
What toxin(s) inhibit neuronal Na+ channels?
Tetrodotoxin
Saxitoxin
Both inhibit muscular Na+ channels as well
Botulinum and tetanus toxins
Both are internalized by neurons and cleave key members of the SNARE complex (synaptobrevin, SNAP-25, and syntaxin)
Botulinum toxin
Botulism - paralysis progresses symmetrically downward, usually starting with the eyes/face, to the throat, chest and extremities (sxs: dilated pupils, blurred vision, bradycardia, hypotension, hypohidrosis, urinary retention, costipation - frequently first sign esp. in infants)
Tetanus toxin
Usually encountered because of infection with Clostridium tetani
Much of the toxin is transported by retrograde axonal transport to postsynaptic membranes of the motor nerve dendrites. Tetanus toxin can then jump to other neurons of the spinal cord/CNS accumulating in inhibititory interneurons.
Function of the tetanus toxin heavy chain
To target the inhibitory interneurons of the spinal cord/CNS
Effectively results in excessive activation of excitatory motor outputs without the usual counterbalancing inhibitory modulation
Short motor neurons are the first to be inhibited (lockjaw and other facial sxs)
Inhibitory post synaptic potential (IPSP)
Some neurons release other neurotransmitters at synapses that open K or Cl channels with the effect of hyperpolarizing the post synaptic cell and making it less responsive to Ach depolarization.
Excitatory post synaptic potential (EPSP)
Synapses in which ACh release from the presynaptic cell evokes a depolarizing response in the postsynaptic cell.
Temporal summation
In nerve-to-nerve transmission, a single EPSP is usually too small to start an action potential in the postsynaptic cell. However, if several stimuli arrive in close succession, their EPSPs can summate to depolarize the threshold.
Presynaptic facilitation and inhibition
Serotonin - facilitation - turns off K channels and in effect
How do NS synapses differ from the neuromuscular junction?
- CNS synapses a single presynaptic action potential produces only a small change in postsynaptic membrane potential.
Neuromuscular junction - a single presynaptic action potential produces a large depolarization of the muscle cell and triggers a postsynaptic action potential.
- Synapses between neurons can either be excitatory or inhibitory. Synapses at skeletal muscle are always excitatory.
- ACh is the neurotransmitter at neuromuscular synapses and is also used in CNS.
- A skeletal muscle receives synaptic input from only one neuron, a single motor neuron. A neuron in the NS may receive synaptic connections from thousands of different neurons. The output of a neuron depends on the integration of all the inhibiatory and excitatory inputs active at a given instant.
When activated, the ACh receptor will be equally permeable to what ions?
Na+ and K+
End-plate potential (EPP)
The EPP is the depolarization at the neuromuscular junction caused by the opening of the ACh receptor channels
MEPPs
Miniature end-plate potentials (~0.4 mV)
Additive and sum to form an end-plate potential (EPP)
Which of the following is least likely to increase the activity of Na/K ATPase?
Increasing extracellular potassium (already pretty high compared to inside cell)
Which of the following is not phosphorylated during the catalytic active transport cycle?
Lysosomal proton ATPase
Depolarized (more positive)
10 mM
Addition of ouabain (a cardiac glycoside and inhibitor of Na/K ATPase) to myocardial cells will:
Increase intracellular volume
The primary determinant of ECF volume is?
ECF sodium concentration
