Physiologic Control & Membrane Transport

Question 1

Allostasis

Answer 1

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.

Question 2

Compensation vs. Decompensation

Answer 2

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

Question 3

Core Body Temp. Regulation

Answer 3

Closed negative feedback loop

Overal regulation sensed and localized to hypothalamus or spinal cord

Question 4

Set point

Answer 4

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

Question 5

If temperature sensors sense cold temp

Answer 5

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

Question 6

Endogenous pyrogens

Answer 6

Cytokines such as some interluekins and tumor necrosis factor

Endogenous pyrogens increase prostaglandin E2 (PGE2) production in the hypothalamus

Question 7

PGE2

Answer 7

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.

Question 8

Error signal

Answer 8

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

Question 9

Blood glucose regulation

Answer 9

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

Question 10

Homeostasis

Answer 10

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

Question 11

Difference between equilibrium and steady state (dynamic equilibrium)

Answer 11

Dynamic equilibrium - energy must be consumed

Question 12

Negative feedback examples

Answer 12

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

Question 13

Componenets of a homeostatic reflex

Answer 13

Question 14

Difference in temperature regulation of exercise and fever?

Answer 14

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.).

Question 15

Three main factors of diffusion across cell membrane

Answer 15

Concentration gradient

Channel conductance

Number of open channels

Membrane Conductance = #Channels open x Channel conductance

Question 16

Pores

Answer 16

Always open, but generally few in number and have a low channel conductance

Question 17

Gated channels

Answer 17

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

Question 18

Protein Carriers

Answer 18

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

Question 19

Active Transport

Answer 19

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

Question 20

Cotransporters/uniporters

Answer 20

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

Question 21

Antiporters

Answer 21

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

Question 22

What molecules can diffuse acrosse the lipid bilayer?

Answer 22

Small w/ and/or lipophilic

Gases: O₂, CO₂, NO

Water, urea, EtOH, and steroid hormones

Question 23

Relationship between diffusion distance and time for diffusion

Answer 23

Diffusion is a slow process (figure to the left). The time for diffusion increases with the square of the diffusion distance.

(∆x)² = 2Dt

Question 24

GLUT 1

Answer 24

K_m = 3-7

Ubiquitous distribution in tissues and cultured cells

Fx: basal glucose uptake: transport across blood tissue barriers

Question 25

GLUT 2

Answer 25

K_m = 17 Liver, islets, kidney, small intestines Fx: High-capacity, low-affinity transport

Question 26

GLUT 3

Answer 26

K_m = 1.4 Brain and nerve cells Fx: Neuronal transport

Question 27

GLUT 4

Answer 27

K_m = 6.6 Muscle, adipose, heart Fx: Insulin-regulated transport in muscle and adipose

Question 28

GLUT 5

Answer 28

Intestine, kidney, and testis Transport of fructose

Question 29

P-Type ATPases or pumps

Answer 29

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

Question 30

V-type ATPase pump

Answer 30

Vacuolar or lysosomal proton pumping ATPases acidify intracellular organelles

Question 31

F-type ATPase or pump

Answer 31

Mitochondrial F₁F₀ ATPase - ATP synthase

Question 32

ABC Transporters

Answer 32

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

Question 33

Short-Term Regulation of Na/K ATPase

Answer 33

Short-term regulation: 1. K_m for intracellular Na = 15 mM and [Na] = 10 mM 2. K_m 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

Question 34

Long-Term Regulation of Na/K ATPase

Answer 34

1. Hormones: insulin, thyroxine, mineralcorticoids (aldosterone) - **activate expression of sodium pump genes** in many tissues including skeletal muscle and kidney 2. Prolonged elevation of intracellular sodium activates pump gene expression

Question 35

Na-glucose co-transporter

Answer 35

Question 36

Na-Ca Exchanger (NCX)

Answer 36

## Footnote Secondary active transport

Question 37

Na-H Exchanger (NHE)

Answer 37

## Footnote Secondary active transport

Question 38

Na/K/Cl Cotransporter (NKCC)

Answer 38

## Footnote Secondary active transport

Question 39

Secondary active transport for epithelial absorption of glucose

Answer 39

Analagous to transport of AA's across epithelial cells (different transporters)

Question 40

Difference between channels and pores

Answer 40

Channels are gated Pores are not (always open)

Question 41

Fick's first law of diffusion

Answer 41

The diffusion flow (flux) is proportional (diffusion constant) to the concentration gradient (force) J_i = -D_iA ∆C_i/∆x (Units for Ji are mmol/sec, units for Di are cm2/sec) or **J_v = K_f ∆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)

Question 42

Van't Hoff Law

Answer 42

𝜋 = 𝑅𝑇(i𝐶) ## Footnote 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)

Question 43

Osmolarity vs. Tonicity

Answer 43

Tonicity = osmolarity x reflection coefficient

Question 44

Hdryostatic and Oncotic force

Answer 44

Question 45

Nernst Equilibrium Equation

Answer 45

Defines the electrical equilbrium potential (voltage) across a membrane due to the unequal distribution (concentration gradient) of permeant ion. ## Footnote Takes the base-ten log of the **concentration of ion C outside of cell over concentration of ion C inside of cell**

Question 46

Which direction ions move (in or out of the cell)

Answer 46

Question 47

The Na/K ATPase and Membrane Potential

Answer 47

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).**

Question 48

Voltage-gated Na⁺ channels

Answer 48

**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.

Question 49

Voltage-gated K⁺ Channels

Answer 49

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.

Question 50

Action Potential | Diagram w/ labels

Answer 50

Question 51

Absolute vs. relative refractory period

Answer 51

**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

Question 52

Basic structure of voltage-gated channel subunit

Answer 52

Question 53

Voltage sensor

Answer 53

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

Question 54

The pore domain

Answer 54

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)

Question 55

Tetrodotoxin (TTX)

Answer 55

Puffer fish toxin that blocks fast voltage-gated Na channels (causing paralysis and death)

Question 56

Tetra ethyl ammonium (TEA)

Answer 56

Voltage-gated potassium channel blocker

Question 57

Knee jerk

Answer 57

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

Question 58

Synapses | Types - diagram

Answer 58

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

Question 59

Steps in process of transmission at chemical synapses

Answer 59

Question 60

Presynaptic action potential and acetylcholine release

Answer 60

Question 61

Nicotinic acetylcholine receptor

Answer 61

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**

Question 62

What toxin(s) inhibit ACh release?

Answer 62

Tetanus toxin Botulinum toxin

Question 63

What toxin(s) inhibits K⁺ channels?

Answer 63

Dendrotoxin

Question 64

What toxin(s) inhibit acetylcholinesterase?

Answer 64

Physostigmine Diisopropyl flourophosphate (DFP)

Question 65

What toxin(s) inhibit the muscular Na⁺ channels?

Answer 65

Tetrodotoxin Saxitoxin μ-conotoxin ## Footnote Tetrodotoxin and saxitoxin both inhibit neuronal Na⁺ channels as well

Question 66

What toxin(s) inhibit the AChR channel?

Answer 66

d-Tubocararine α-bungarotoxin ## Footnote Toxins from a frog and snake respectively that are antagonist for the ACh receptor and block synaptic transmission

Question 67

What toxin(s) inhibit voltage-gated Ca²⁺ channels?

Answer 67

ω−conotoxin ## Footnote Toxin from snail and blocks the synaptic voltage gated Ca channel

Question 68

What toxin(s) inhibit neuronal Na⁺ channels?

Answer 68

Tetrodotoxin Saxitoxin ## Footnote Both inhibit muscular Na⁺ channels as well

Question 69

Botulinum and tetanus toxins

Answer 69

Both are internalized by neurons and cleave key members of the SNARE complex (synaptobrevin, SNAP-25, and syntaxin)

Question 70

Botulinum toxin

Answer 70

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)

Question 71

Tetanus toxin

Answer 71

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.

Question 72

Function of the tetanus toxin heavy chain

Answer 72

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)

Question 73

Inhibitory post synaptic potential (IPSP)

Answer 73

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.

Question 74

Excitatory post synaptic potential (EPSP)

Answer 74

Synapses in which ACh release from the presynaptic cell evokes a depolarizing response in the postsynaptic cell.

Question 75

Temporal summation

Answer 75

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.

Question 76

Presynaptic facilitation and inhibition

Answer 76

Serotonin - facilitation - turns off K channels and in effect

Question 77

How do NS synapses differ from the neuromuscular junction?

Answer 77

1. 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. 2. Synapses between neurons can either be excitatory or inhibitory. Synapses at skeletal muscle are always excitatory. 3. ACh is the neurotransmitter at neuromuscular synapses and is also used in CNS. 4. 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.

Question 78

When activated, the ACh receptor will be equally permeable to what ions?

Answer 78

Na⁺ and K⁺

Question 79

End-plate potential (EPP)

Answer 79

The EPP is the depolarization at the neuromuscular junction caused by the opening of the ACh receptor channels

Question 80

MEPPs

Answer 80

Miniature end-plate potentials (~0.4 mV) Additive and sum to form an end-plate potential (EPP)

Question 81

Which of the following is least likely to increase the activity of Na/K ATPase?

Answer 81

Increasing extracellular potassium (already pretty high compared to inside cell)

Question 82

Which of the following is not phosphorylated during the catalytic active transport cycle?

Answer 82

Lysosomal proton ATPase

Question 83

Answer 83

Depolarized (more positive)

Question 84

Answer 84

10 mM

Question 85

Addition of ouabain (a cardiac glycoside and inhibitor of Na/K ATPase) to myocardial cells will:

Answer 85

Increase intracellular volume

Question 86

The primary determinant of ECF volume is?

Answer 86

ECF sodium concentration