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302 Cards in this Set

  • Front
  • Back
Extracellular fluids are composed of what types of fluids?
-plasma
-interstitial fluid and lymph
-transcellular fluid
What are the components of the "extravascular compartment"?
-interstitial fluid
-intracellular fluid
What percentage of body weight is accounted for by intracellular fluids?
30-40%
What percentage of body weight is accounted for by extracellular fluids?
27%
Is K+ concentration higher in intracellular or extracellular fluids?
intracellular fluids

(ICF = 150 mM, ECF = 5.5 mM)
Is protein concentration higher in intracellular or extracellular fluids?
intracellular fluids
Is Na+ concentration higher in intracellular or extracellular fluids?
extracellular fluids

(ICF = 15 mM, ECF = 150 mM)
Is Ca2+ concentration higher in intracellular or extracellular fluids?
extracellular fluids

(ICF = 0.0001 mM, ECF = 2.0 mM)
Is Cl- concentration higher in intracellular or extracellular fluids?
extracellular fluids

(ICF = 10 mM, ECF = 125 mM)
Is Mg2+ concentration higher in intracellular or extracellular fluids?
intracellular fluids

(ICF = 58, ECF = 3)
What fluids are in constant exchange with each other at the capillaries?
plasma and interstitial fluid
What is interstitial fluid and its purpose?
the fluid that permeates the space between cells and is responsible for supplying nutrients and removing wastes
From what is interstitial fluid formed?
formed by ultrafiltration of the plasma in the capillaries
What is transcellular fluid?
fluid trapped within the closed cavities of the body such as joints, cerebral ventricles and spinal cord, intra-ocular fluid, digestive juices, or is bound within the matrices of cartilage and bone
What are the basic components of the cell membrane?
-phospholipids
-cholesterol
-proteins
-small amount of water
What holds the membrane components in place, which allows regions of membrane to have higher concentrations of certain proteins?
the cytoskeleton
What is simple diffusion?
-net movement of an UNCHARGED substance whenever a concentration gradient exists

-it results from the random motion intrinsic to all atoms or molecules
Through what type of transport does alcohol cross the cell membrane?
simple diffusion
Through what type of transport does water cross the cell membrane?
simple diffusion
Through what type of transport do ions such as Na+, Ca2+, K+, and Cl- cross the cell membrane?
facilitated diffusion (or facilitated transport)
What is the chemical driving force?
the force that drives movement of substances across the membrane down a concentration gradient
What is the difference between simple diffusion and facilitated/active transport in terms of temperature sensitivity?
-simple diffusion has low temperature sensitivity

-facilitated diffusion and active transport are temperature dependent
What is the difference between simple diffusion and facilitated/active transport in terms of saturation?
-simple diffusion has no saturation with increased concentration

-in facilitated diffusion or active transport, there is a maximal rate of transport because there are a finite number of receptors in the membrane
What is the difference between simple diffusion and facilitated/active transport in terms of specificity?
-simple diffusion is sensitive to lipid solubility and molecular size, but not to slight structural differences

-the receptors of facilitated/active transport recognize ligands on the basis of their structure
Through what type of transport do gases move across the cell membrane?
simple diffusion
Why does water pass through the cell membrane by simple diffusion more rapidly than is predicted by its lipid solubility alone?
-water has both "polar" and "non-polar" characteristics

-there also may be watery pores in the membrane or water may pass between adjacent phospholipid molecules without dissolving in membrane
Through what type of transport does urea cross the cell membrane?
simple diffusion
The cell membrane can be described electrically as an "equivalent circuit." What are the electrical properties of the cell membrane?
-resistance (membrane acts as an insulator)
-capacitance
-electromotive force (EMF)
What causes water movement across membranes?
-concentration gradient
-hydrostatic pressure
What is osmosis?
water movement by simple diffusion because of a concentration gradient
Where does hydrostatic pressure play a role in water movement?
hydrostatic pressures are normally negligible across cell membranes, but are very important for water movements into and out of capillaries
What is the osmolarity of an isotonic solution?
300 mOsm
What is the typical osmolarity inside a cell?
300 mOsm
What is the osmolarity of a hypotonic solution?
< 300 mOsm
What is the osmolarity of a hypertonic solution?
> 300 mOsm
What is facilitated diffusion?
movement of substances by protein "carriers" that mediate transmembrane diffusion down an electrochemical gradient
Through what type of transport do ions move across a cell membrane?
facilitated diffusion
Through what type of transport does glucose move across the cell membrane?
facilitated diffusion
Through what type of transport do amino acids move across the cell membrane?
facilitated diffusion
Through what type of transport do vitamins move across the cell membrane?
facilitated diffusion
What is competitive inhibition?
-structurally related substances will compete with the permeant molecule and inhibit its transport

-characteristic of facilitated diffusion and active transport
What is active transport?
transport of substances against their electrochemical gradients that requires energy
What is primary active transport?
directly uses energy to move ions against their electrochemical gradient

ex. Na+/K+ ATPase
What is secondary active transport?
-indirectly uses energy to move ions against their concentration gradient

-the transport of one substance against its concentration gradient is linked to the simultaneous co-transport of a second substance down its concentration gradient, and it is this latter gradient which is maintained by active transport.
What is an example of secondary active transport?
Na+-Ca2+ exchanger

-relies on Na+ influx down its concentration gradient to drive Ca2+ against its concentration gradient (the Na+ gradient is maintained by the Na+-K+ ATPase pump)
What is Channel A?
a passive channel that always remains open
What is Channel B?
a voltage-activated channel that has a voltage sensor and an activation gate
What is Channel C?
a voltage-activated channel that has a voltage sensor, activation gate, AND an inactivation gate; thus Channel C may exist in three different conformations, open, closed, and inactivated
What is Channel D?
a receptor-activated channel
What accounts for the selectivity of ion channels?
-ions are associated with a coating of water molecules because of ionic bonding between the dipole of water and the charged ion

-ion channels are water-filled pores that must allow for the ion plus the waters-of-hydration
What is the mechanism of the voltage sensor on ion channels?
-when the sensor is stimulated, the probability of the channel to be open increases

-when the sensor is not stimulate, the probability of the channel to be open is low
What kind of channel is the K+ ion channel?

(A/B/C/D)
Channel B
What kind of channel is the Na+ channel?

(A/B/C/D)
Channel C
What kind of Channel is the Ca2+ channel?

(A/B/C/D)
Channel C
How can Channel A function be modified?
-change in number of channels
-change in permeability of channels
How can Channel B function be modified?
-change in number of channels
-change in permeability of channels
-change in sensitivity to voltage
How can Channel C function be modified?
-change in number of channels
-change in permeability of channels
-change in sensitivity to voltage
-change in gate function
How can Channel D function be modified?
-change in number of channels
-change in permeability of channels
-change in ligand binding
What are the driving forces that act on ions?
-concentration gradient
-electrical gradient

The net force on a charged species (ion) will take both the concentration (chemical) gradient and electrical gradient into account and results in the electrochemical driving force.
What is the equilibrium potential of an ion?
-when there is no net driving force on an ion

-the transmembrane potential which provides enough electrical driving force to equal the chemical driving force
What is the Nernst Equation?

Provide equation.
The mathematical relationship which defines the potential at which the driving forces are equal and opposite (i.e. no net driving force).

Vm = (RT/ZF) ln (X1/X2)

R = gas constant
T = absolute temperature
Z = valence of the ion
F = Faraday constant
X1 = concentration of the ion outside
X2 = concentration of the ion inside
What is the equilibrium potential of Na+?
+60 mV
What is the equilibrium potential of K+?
-86 mV
What is the equilibrium potential of Ca2+?
+150 mV
What is the equilibrium potential of Cl-?
-60 mV
What are the passive (intrinsic) electrical properties of excitable cells?
1) electromotive force (any source of electrical potential)
2) capacitance (two electrical conductors separated by an insulator; these conductors can store charge due to attraction between unlike charges)
3) resistance ("internal" and "membrane")
What is internal resistance?
The internal resistance is a function of the diameter of the cell or axon. The greater the diameter the
lower the internal resistance; by analogy water flows more easily through a large pipe than a small
pipe.
What is the resting membrane potential of neurons?
-65 mV (-50 to -70 mV)
Why is the resting membrane potential fairly close to the equilibrium potential of K+?
the membrane is most permeable to the potassium ion (the passive channels that are always open are more permeable to K+)
Is there flow of ions at the resting membrane potential?
yes, there is a constant flow ions via passive channels that are always open, but there is no net ion flow
What is the Goldman Equation?
The Goldman Equation takes into account the membrane permeability to determine the potential difference across the membrane. Note that V (the membrane potential) will vary with P (the permeability) and the electrochemical driving force (the ratio of the concentrations inside and outside and the valence of the ion (one of the constants).
What essentially determines the membrane potential of neurons?
the normal neuronal membrane potential is determined by the differential permeability of the membrane to K+ over Na+
What blocks voltage-gated Na+ channels?
tetrodotoxin (TTX)
How many Na+ and K+ ions are transported by the Na+-K+ ATPase pump?
3 Na+ out for 2 K+ in, thus there is a net movement of 1 positive charge out
What is hyperpolarization?
increasing the negativity of the membrane potential (more negative)
What is depolarization?
decreasing the negativity of the membrane potential (more positive)
What happens if tetrodotoxin (TTX) is applied to a neuron?
the fast voltage-sensitive Na+ channels are blocked, blocking the resting Na+ flux and leading to a slight hyperpolarization
What is the electrochemical driving force?
the net force on an ion in solution (electrical driving force plus chemical driving force)
What primary channel(s) is/are involved in the action potential?

(A/B/C/D)
B and C
What are the key features of the inactivation gate?
-slower kinetics compared to the activation gate

-tends to stay closed (inactive) until the membrane is repolarized
Why is the depolarization phase of the action potential not long-lasting?
-the enhanced permeability of the membrane to Na+ is very transient
-the permeability of the membrane to K+ increases as K-channels respond more slowly to depolarization
What is "threshold"?
the membrane potential at which the inward Na+ current (increased by the depolarization) just exceeds the outward K+ current (primarily through passive channels)
What do normal neuronal membranes contain at resting membrane potential?
-passive K+ channels
-passive Cl- channels
-fast voltage-sensitive Na+ channels
What stimulates Na+ channels to open?
depolarization
What toxin blocks K+ channels?
tetraethylammonium (TEA)
Is threshold potential a fixed, unchanging value?
NO. since threshold occurs at the voltage when inward Na+ current just overcomes the outward K+ current, the threshold voltage is affected by anything that alters the magnitudes of these currents
What happens to the threshold potential in cases of Ca2+-deficiency?
Na+ channels become more sensitive to voltage changes, so the threshold is moved toward the resting membrane potential (more channels will open for a given depolarizing stimulus due to increased sensitivity)
What is accommodation?
-occurs when significant numbers of Na+ channels become inactivated and the overall sensitivity of the neuron to depolarization is decreased

-this, in turn, increases the threshold membrane potential
What is the refractory period?
the time folllowing an AP during which a neuron will not fire another AP
What is the absolute (effective) refractory period?
the time folllowing an AP during which a neuron will not fire another AP regardless of the stimulation strength because there has not yet been sufficient time for reactivation of Na+ channels so little inward current can be produced
What is the relative refractory period?
the time folllowing an AP during which a neuron will not fire another AP unless there is a stimulus of increased strength that can overcome the enhanced K+ current
What is the local circuit current?
the passive depolarization of adjacent membrane segments; the depolarization that the current elicits is the "local response"
What is the length constant (lambda)?
-a measure of how far away from the stimulus site a membrane potential change will be detectable

-represents the length of an axon needed for a charge to decay to 37% of the initial amplitude
What happens as the length constant (lambda) increases?
the time it takes to drive the adjacent membrane to threshold decreases and the AP is reproduced more rapidly and is conducted along the length of the axon more rapidly
How can the length constant (lambda) be increased?
lambda increases when the relative resistance of the internal compartment decreases compared to the membrane

This can happen by:

1) Increasing the axon diameter (surface area to volume ratio decreases)

2) Increasing the resistance of the membrane
What is orthodromic conduction?
action potential is propagated anterogradely
What is antidromic conduction?
action potential is propagated retrogradely
What influences the extent of the local response over distance and velocity of propagation?
1) amplitude of the AP
2) the threshold potential
3) the diameter of the axon (i.e. internal resistance)
4) the membrane resistance
Why is propagation of action potentials increased in myelinated axons?
the effective resistance of the membrane in internode regions is greatly increased by the myelin sheath
What is saltatory conduction?
action potentials only fire in the node regions, so excitation appears to jump from node to node
Why do action potentials skip the internode regions in myelinated axons?
1) There are very few Na+ channels
2) The myelin has decreased the capacitance and increased the resistance of the internode membrane
3) The nodal membrane has an abundance of Na+ channels
In a graded stimulus response relation in the nerve trunk, axons are "recruited" according to which properties?
A. Size and myelination. Size because larger axons disrupt more field and myelination because they trap more charge (higher membrane resistance and less capacitance).

B. Location. Closer is better, but this is far less important than size and myelination.
What are compound action potentials?
responses recorded from outside a nerve that reflect the action potentials being carried by the entire population of axons in the nerve
What is an electroneurogram (ENG)?
a measurement of action potentials in a peripheral nerve
What is an electromyogram (EMG)?
a measurement of action potentials of muscle cells
What happens in cases of myelin damage or demyelination?
Na+ channels that are normally restricted to the Nodes of Ranvier become spread out over the entire axon membrane, resulting in a decrease in membrane resistance across the internode regions and decreasing conduction velocity of action potentials, which could potentially block AP conduction
Even though central axons are not usually able to regenerate significantly, how does some remyelination occur in the CNS?
-remyelination by newly generated oligodendrocytes (precursor cells)
-remyelination by Schwann cells that enter damaged CNS from the PNS
What is a demyelination disease of the CNS?
multiple sclerosis
What is a demyelination disease of the PNS?
Guillain-Barré Syndrome
What is Transcranial Magnetic Stimulation (TMS)?
use of a brief magnetic field to induce weak, repetitive electric currents that stimulate neurons of the brain (CNS) as a potential therapy for many CNS pathologies
What are transcranial magnetic motor-evoked potentials?
use of small magnetic transducers to stimulate peripheral nerves in motor pathways as both an assessment and potential therapy of lower extremity function following a spinal cord injury
What are the general types of chemical synapses?
-neuron to muscle, referred to as a neuromuscular junction and

-neuron to neuron
What are the characteristics of chemical synaptic transmission?
1) there is a time delay across the synapse

2) transmission is unidirectional

3) transmission may be influenced by previous activity

4) there may be temporal and spatial summation of transmission

5) transmission may be excitatory or inhibitory
What are the pre-synaptic events of neuromuscular transmission?
An AP propagating down the axon invades and depolarizes the presynaptic terminal region. This causes:

A flow of Ca2+ into the boutons through voltage-activated Ca2+ channels. The elevated Ca2+ triggers:

The fusion of synaptic vesicles with pre-synaptic membrane specializations and the release of "packets" or quanta of acetylcholine into the cleft.
In neuromuscular transmission, what determines the amount of acetylcholine released from the pre-synaptic terminal region?
the amount of transmitter released is directly related to the amount of Ca2+ that enters the bouton, which is directly related to the number, amplitude and duration of the invading action potentials
What are the post-synaptic events of neuromuscular transmission?
4) ACh diffuses across the cleft. This takes time (up to several hundred µs).

5) ACh binds to Nicotinic Acetylcholine receptors in the post-synaptic membrane, opening monovalent cation channels.

6) Channel opening depolarizes the post-synaptic membrane, creating an end-plate potential (EPP).

7) EPPs spread passively to the excitable muscle membrane.

8) Voltage-activated Na+ channels open giving rise to a muscle AP.

9) Termination of the transmission process occurs via hydrolysis of ACh by acetylcholinesterase present in the junction.
When is the end-plate potential big enough to generate an action potential in neuromuscular transmission?
It is always big enough to generate an action potential.

1-to-1 relationship
What is Myasthenia Gravis?
an autoimmune disease where nicotinic acetylcholine receptors of the neuromuscular junction are attacked
What is Lambert-Eaton Myasthenic Syndrome?
an autoimmune disease where voltage-gated calcium channels that are present presynaptically in the neuromuscular junction are attacked
With what other condition is Lambert-Eaton Myasthenic Syndrome often linked?
small cell lung cancer
What is Guillain-Barre syndrome?
-an autoimmune disease that is often triggered by a GI infection of campylobacter jejuni

-patients express antibodies to gangliosides, proteins that are associated with the motor nerve terminal

-damage to the nerve terminal leads to a secondary demyelination and damage to motor axons
What is the effect of the paralytic toxin curare?
prevents an action potential
What is the reversal potential?
the membrane potential at which the synaptic response is neither depolarizing nor hyperpolarizing (i.e. net ion flow is 0)
What are miniature end-plate potentials (MEPPs)?
small, random depolarizations that spontaneously release individual quanta of ACh of uniform quantity
What is a quanta of ACh?
the amount of ACh released from one presynaptic vesicle
What are the criteria for a chemical to be considered a transmitter?
1) synthesized by the pre-synaptic neuron

2) present in and released from pre-synaptic structures in sufficient quantity

3) if applied exogenously, the post-synaptic action must mimic that of actual transmission at the synapse

4) a specific mechanism must exist to terminate the action
What is latency?
the length of time between the stimulation and start of the response
What are the characteristics of electrical synaptic transmission?
1) there is little time delay across the synapse - faster than chemical

2) transmission is bi-directional

3) may be influenced by previous activity - yes, but over a longer time-scale

4) there may be temporal and spatial summation of transmission - yes

5) transmission of action potentials is simple - a “one-to-one” relationship
What is the intercellular connection in an electrical synapse?
The intercellular connection is via gap junctions. They allow ions and water soluble molecules to pass from cell to cell…up to 1000MW.

This is large enough to allow amino acids and even small peptides (5-7 aa long) to pass through.
What are the proteins that make up gap junctions?
connexins (have 6 subunits)
What is the effect of Ca2+ levels on gap junctions?
high Ca2+ = closed state
low Ca2+ = open state
What is the effect of pH on gap junctions?
low pH = closed state
high pH = open state
What is the selectivity of gap junctions?
gap junctions are not selective for any ions, but do have a size limitation
What are the types of post-synaptic responses in a neuron-neuron synapse?
In a neuron-to-neuron synapse the post-synaptic response, known as a PSP (post-synaptic potential) may be excitatory or inhibitory (EPSP or IPSP).
When is an EPSP large enough to induce an action potential?
Most EPSPs won’t be large enough to induce an action potential by themselves. Neurons receive inputs from many different presynaptic neurons.
What is the "goal" of an EPSP?
The “goal” of an EPSP is to push the membrane potential above threshold. So, as long as the reversal potential of the channels involved is positive to threshold, EPSPs can be successful.
What is the reversal potential of channels involved in ACh and glutamate signaling in neuron-to-neuron synapses?
The channels involved in ACh and glutamate signaling, the two most abundant excitatory transmitters, have reversal potentials close to 0mV because they allow both Na+ and K+ to flow with a slight preference for Na+.
How is an EPSP induced from both an increase and decrease in membrane permeability?
-increased membrane permeability to Na+ and K+ sets the reversal potential for the EPSP near 0mV, thus making the reversal potential of the channels positive to threshold

-a decrease in permeability to K+ reduces the role of Ek in determining the level of the membrane potential and increases the excitability of the neuron
What transmitters act to close voltage-gated K+ channels contributing to the resting membrane permeability to K+ and repolarization during the AP?
ACh, norepinephrine, serotonin
What is the "trigger zone"?
the patch of membrane with the lowest threshold potential because it has the highest concentration of voltage-gated Na+ channels
What are the typical effects of IPSPs?
increase in permeability of the post-synaptic membrane to K+ and/or Cl-, which results in hyperpolarization of the membrane potential
What are examples of neurotransmitters for inhibitory transmission in an electrical synapse?
-gamma-aminobutyric acid (GABA)
-glycine
What does GABA do?
an inhibitory neurotransmitter that activates a receptor that directly opens a gated Cl- channel
What does glycine do?
an inhibitory neurotransmitter that opens Cl- channels
What is presynaptic inhibition?
Pre-synaptic inhibition is effective by reducing the amount of Ca2+ that enters the excitatory terminal when it is invaded by an AP. If the amount of Ca2+ is reduced, then less transmitter is released.
What are mechanisms behind presynaptic inhibition?
-inactivation of Na+ channels, hench shorter AP duration

-inactivation of voltage-gated Ca2+ channels required for Ca2+ influx and vesicle fusion with the membrane
What is presynaptic facilitation?
if an axo-axonic synapse can have the effect of increasing the amount of Ca2+ that flows into the excitatory terminal, more transmitter will be released
What is spatial summation?
occurs when simultaneously propagating post-synaptic potentials from two or more inputs combine on the membrane
What is temporal summation?
occurs when a single input fires rapidly enough that a second EPSP occurs before the first is over
What is synaptic divergence?
when one source provides output to many targets
What is synaptic convergence?
when multiple sources arrive onto one neuron or class of neurons
What is reciprocal or recurrent inhibition?
an excitatory synapse onto an inhibitory interneuron that in turn synapses back onto the excitatory neurons
What is an example of recurrent inhibition?
the relationship between Renshaw cells and motoneurons in the spinal cord
What are Renshaw cells?
inhibitory interneurons that serve to limit the activity of motoneurons using a recurrent inhibitory circuit
What is the neurotransmitter of the motoneuron-Renshaw cell synapse?
ACh (excitatory cholinergic input)
What is the neurotransmitter of the Renshaw cell-motoneuron synapse?
glycine (inhibitory glycinergic input)
What are the primary inhibitory neurotransmitters in the CNS?
glycine and GABA
What is the action of antagonists?
compete with agonists by binding to receptors, but do not activate them
What is the difference between a ligand and an agonist?
Ligand: molecule that can bind to a receptor

Agonist: ligand that binds to, and activates a receptor
What are the receptor types for the excitatory neurotransmitter glutamate?
-ionotropic (3 of 4)
-metabotropic (4th recceptor type)
What are ionotropic receptors?
-ligand-gated receptors that are activated by glutamate or certain glutamate analogues

-their activation results in a rapid increase of the membrane permeability to two or more cations including Na+ and K+ and in some cases, Ca2+
What are metabotropic receptors?
glutamate receptors that utilize second messenger systems
What are the classical types of ionotropic glutamate receptors?
-NMDA
-kainate
-AMPA (originally called quisqualate receptor)
What are differences between NMDA and non-NMDA (kainate and AMPA) ionotropic receptors?
-NMDA receptors require the presence of a second amino acid (glycine)

-NMDA receptors allow Ca2+ to enter the cell

-ion flow through NMDA receptors is limited at normal resting potentials by Mg2+
What is the voltage-dependent blockade of the NMDA receptor channel?
Mg2+ ions plug the NMDA receptor ionophore at membrane potentials close to rest
What is the reversal potential of nicotinic acetylcholine receptors?
close to 0 mV
What is the reversal potential of ionotropic glutamate receptors (AMPA, kainate, and NMDA)?
close to 0 mV
Other than glutamate, what other amino acid is capable of activating glutamate receptors?
aspartate
Other than its functioning as a neurotransmitter in the CNS, where else is glutamate utilized?
glycolysis and Krebs cycle

(neurons have two inter-related “pools” of glutamate, one called the metabolic pool and the other called the transmitter pool)
Describe the glutamate cycle (synthesis and reuptake)?
1) glutaminase converts glutamine to glutamate in the axon

2) glutamate is released and taken-up by local astrocytes

3) glutamine synthetase converts glutamate to glutamine in the astrocyte

4) glutamine can be passed from astrocyte to neuron
What are examples of NMDA antagonists?
APV or MK-801
What is the retrograde signal?
activation of NMDA and non-NMDA receptors on post-synaptic membrane can act on pre-synaptic vesicles by increasing the amount of glutamate stored in the vesicles
What is long-term potentiation?
the release of a retrograde signal can increase the amount of glutamate stored in pre-synaptic vesicles, which results in potentiation of post-synaptic responses that can last hours
What is glutamate toxicity or excitotoxicity?
when glutamate receptors are excessively activated, the amount of Ca2+ that enters the neurons can exceed the cells' ability to sequester ir remove it from the intracellular space
What is a contributing factor in many types of epilepsy?
the voltage-dependence of NMDA channel activation, and the very large conductances that result when NMDA channels are activated while a neuron is already in a depolarized state
What is the problem with glutamate-receptor antagonist therapy for brain/spinal cord injury?
glutamate is such an abundant transmitter that is involved in many CNS functions, including control of respiration and cardiovascular function
Are receptors for GABA and glycine ionotropic or metabotropic?
both are ionotropic
The channels for GABA and glycine receptors are selective for which ion?
Cl-
What is the effect of GABA or glycine receptor activation on a depolarized neuron?
the membrane potential will become more negative and this will prevent or reduce the production of action potentials
What is the reversal potential of GABA and glycine receptor channels?
equivalent to the Cl- equilibrium potential, which is at or near the resting membrane potential of -65 to -70 mV
Which inhibitory receptors are located presynaptically and postsynaptically?
postsynaptic: GABA-A and glycine
presynaptic: GABA-B
What is an antagonist of the glycine receptor?
strychnine, a well-known poison
What drugs facilitate the binding of GABA to GABA-A receptors, thus enhancing the postsynaptic responses to GABA?
-the benzodiazepine family of antiolytics
-the barbiturate family of hypnotics
What is a GABA-B receptor antagonist?
Baclofen
Describe the GABA cylce (synthesis/reuptake).
1) glutaminase converts glutamine to glutamate

2) glutamic acid decarboxylase (GAD) converts glutamate to GABA

3) GABA is released from axon terminal and is taken-up by glial cells in the region of the synapse

4) GABA becomes part of the Krebs cycle, where it produces glutamate

5) glutamine synthetase converts glutamate to glutamine, which is then passed to the adjacent neuron
Describe the acetylcholine cycle.
-ACh is synthesized from Acetyl CoA and choline via the enzyme Choline Acetyltransferase, otherwise known as Chat

-ACh is broken down by acetylcholinesterase; the components are taken-up by neurons to be recycled
What is used as a marker for GABAergic neurons?
glutamic acid decarboxylase (GAD)
What is used as a marker for cholinergic neurons?
Choline Acetyltransferase (Chat)
How do acetylcholine and glutamate receptors safeguard against non-specific activation of the receptor by low levels of transmitter?
two moleucles of ACh/glutamate must bind to its receptors for activation
What toxin prevents presynaptic vesicles carrying ACh from fusing with the membrane?
botulinum toxin
What are examples of nicotinic acetylcholine receptors?
Curare and Hexamethonium
What is an antagonist for muscarinic acetylocholine receptors located on the postsynaptic membrane?
atropine
What is Physostigmine?
It is an inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction
What drug blocks the reuptake of choline, the rate-limiting step in acetylcholine synthesis?
Hemicholinium
What are examples of aminergic transmitters, or catecholamines?
dopamine, norepinephrine, epinephrine
What is an example of an indolamine?
serotonin (5-HT)
What are the biogenic amines?
catecholamines (dopamine, norepinephrine, epinephrine) and the indolamine serotonin (5-HT)
What are examples of neuropeptides (peptide neurotransmitters)?
substance P and the opioids Met- and Leu-enkephalin
What is volume transmission?
the transmitter molecule may be release some distance away from a receptor, and the response is, low, slow and long. This may be via iontropic or metabotropic receptor types
What kind of receptors do biogenic amines use?
metabotropic receptors
What is the rate-limiting enzyme of the synthesis of catecholamine neurotransmitters?
tyrosine hydroxylase (converts tyrosine to L-dopa)
How can the rate-limiting step of catecholamine neurotransmitter synthesis be bypassed?
L-dopa, the immediate precursor to dopamine, can be added into the system and bypass the conversion of tyrosine to L-dopa by tyrosine hydroxylase
What is the normal transmitter for substantia nigra neurons that project to the striatum via the nigrostriatal pathway?
dopamine
What is the cause of Parkinson's Disease?
results from a loss of dopaminergic neurons in the substantia nigra, thus diminishing dopamine output to the striatum
What is one of the treatments of choice for Parkinson's Disease?
L-dopa treatment
After dopamine release, what happens to dopamine if it is not taken-up into the dopaminergic neuron and recycled?
it is broken down by by MAO (monoamine oxidase) or COMT (catechol-O-methyltransferase)
Where is the largest concentration of dopaminergic neurons?
in the substantia nigra, located in the mesencephalon (midbrain) close to the nucleus of the 3rd cranial nerve and red nucleus
What enzyme is used as a marker for Dopaminergic neurons?
tyrosine hydroxylase
What enzyme used as a marker for noradrenergic (norepinephrinergic) neurons?
dopamine beta-hydroxylase, which converts dopamine to norepinephrine
Where is the largest concentration of noradrenergic (norepinephrinergic) neurons?
the pontine nucleus locus ceruleus
In what functions is the locus ceruleus involved?
attention, arousal (flight or fight), sleep
Where is the largest concentration of serotonergic neurons?
raphe nucleus in the reticular formation
What are the effects of serotonin involving the spinal cord?
-flow of sensory information entering the dorsal horn is dramatically reduced

-elicits locomotor-like rhythmic movements of the hindlumbs in laboratory animals when applied to the ventral horn
What happens to serotonin that remains in the extracellular space (not taken-up by nerve terminal)?
degraded by MAO (monoamine oxidase)
What is an important neurotransmitter for motor systems and locomotion?
serotonin
What is the precursor for serotonin?
tryptophan
What drug acts on noradrenergic synapses by increasing the levels of norepinephrine released?
amphetamine
What drug acts on noradrenergic synapses by binding to Alpha-2 adrenergic receptors, which decrease norepinephrine levels?
clonidine
What blocks reuptake of norepinephrine released into noradrenergic synapses?
tricyclic antidepressants and amphetamines
What is the action of MAO at the noradrenergic synapse?
-converts unsequestered NE to DOPEG (3,4-dihydroxyphenylglycol)

-converts NM (normetanephrine, converted from NE by COMT) to MHPG (3-methoxy-4-phenylglycol)
How do serotonergic neurons project widely throughout the brain?
via the medial forebrain bundle
What drugs block serotonin (5-HT) reuptake?
Imipramine and Amitriptyline
What enhances serotonin (5-HT) binding at the postsynaptic receptor?
lysergic acid diethylamide (LSD)
What acts acts as an irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin?
PCPA (p-chlorophenyalanine)
What is the main metabolite of serotonin?
5-HIAA (5-Hydroxyindole acetic acid)
What are enkephalins and substance P, two peptide neurotransmitters, involved in?
involved in the responses to painful stimuli
Where is substance P found?
Substance P is found in dorsal root ganglia, dorsal horn and dorsal column nuclei of the spinal cord, and in many regions of the midbrain
What is the result of substance P release?
slowing of EPSP
What makes the release of substance P unique?
substance P is released both centrally (spinal cord and dorsal column nuclei) and peripherally (from receptor endings)
What responses does substance P participate in?
-peripheral response to pain (inflammation)
-central response to pain (primary afferent transmission)
What transmitter is involved in pain and temperature sensation?
substance P
What are the endogenous opioids that act via opioid receptors?
enkephalins and endorphins
What drugs activate opioid receptors?
heroin and morphine
What is the action of enkephalin and endorphin?
act to control the ascending flow of pain by blocking afferent input at the level of the dorsal horn of the spinal cord
What is the side-effect of the drugs that act on opioid receptors?
slows breathing
What drug acts on the mu opioid receptor?
fentanyl (narcotic)
Describe the "Gate Control Theory of Pain."
-a primary sensory neuron releases substance P at its synapse with a neuron of the spinothalamic tract

-substance P release is controlled by a descending pathway dubbed DNIC (descending noxious inhibitory controls) that has spinal interneurons that release enkephaloin
What is purinergic transmission?
neurotransmission of ATP and adenosine as the neurotransmitters
What is co-transmission?
two different molecules are packaged into each synaptic vesicle
What are examples of co-transmission?
-ATP and adenosine in neuronal terminals

-ACh and calcitonin gene-related peptide (CGRP) at the neuromuscular junction

-ACh and GABA by amacrine cells in the retina
What is calcitonin gene-related peptide (CGRP)?
a modulator of the ACh receptor, acting to increase the force of a resulting muscle contraction by mobilizing the 2nd messenger adenylyl cyclase
What is co-packaged and co-released with almost all neurotransmitters?
ATP, but is only a co-transmitter if the post-synaptic cells have ATP receptors and if there is a response to the released ATP
What are the neurotransmitter functions of nitric oxide (NO)?
-involved in production of long-term potentiation in the hippocampus and cortex (memory)

-involved in nociception (pain) via spinothalamic pathways
How do second messenger systems alter the activity of gated channels?
induce changes via metabolic pathways in the cell that lead to long-term changes in protein synthesis and function
What is the molecule common to all second messenger systems?
G-protein (transmembrane protein)
How are G-proteins activated?
activated by making contact with a ligand-receptor complex (collision-coupled mechanism)
What enzymes give rise to second messengers?
adenylyl cyclase, phospholipase C, phospholipase A2
What does the enzyme adenylyl cyclase produce?
cAMP (second messenger)
What does the enzyme phospholipase C produce?
inositol polyphosphate and diacyl glycerol, IP3-DAG (second messenger)
What does the enzyme phospholipase A2 produce?
arachidonic acid (second messenger)
What are the first messenger, receptor, primary effector, secondary messenger, and secondary effector of the cAMP system?
first messenger (external signal): norepinephrine

receptor: beta-adrenergic receptor

primary effector: adenylyl cyclase

second messenger: cAMP

secondary effector: cAMP-dependent protein kinase
What is the action of cAMP in cytosol?
activates cAMP-dependent protein kinases
What results from activation of cAMP-dependent protein kinases in the cAMP system?
effects channel function and up-regulates protein synthesis
What are the first messenger, receptor, primary effector, second messenger, and secondary effector of the phosphoinositol (IP3-DAG) system?
first messenger (external signal): acetylcholine

receptor: muscarinic ACh receptor

primary effector: phospholipase C

second messenger: IP3, DAG

secondary effector: Ca2+ release (IP3), protein kinase C (DAG)
What is the end-result of the IP3-DAG system?
mobilization of intracellular Ca2+ from the SER, which can have a host of different effects on the cell including increased protein synthesis in the long-term and opening of Ca2+-dependent K+ channels in the short-term
What are the first messenger, receptor, primary effector, second messenger, and secondary effector of the arachidonic acid system?
first messenger (external signal): histamine

receptor: histamine receptor

primary effector: phospholipase A2

second messenger: arachidonic acid

secondary effector: several different enzymes
What is the end-result of the arachidonic acid system?
production of prostaglandins, leukotrienes, and other molecules involved in inflammation and the inflammatory response
What are the key features of a second messenger system?
1) cascade which allows for amplification

2) collision-coupled event requiring a G-protein

3) second messenger, free in the cytoplasm

4) slow, low and long (the response that is)
To which second messenger system is the AMPA-B metabotropic receptor coupled?
IP3-DAG system
Which part of the phospholipid is water-soluble and which part is lipid-soluble?
water-soluble = head of phospholipid (hydrophilic)

lipid-soluble = tail of phospholipid (hydrophobic)
What are alternate names for charged ions?
electrolytes or ionized salts
Are phosphate concentrations higher inside the cell or outside the cell?
inside the cell

(inside = 75 mM, outside = 4 mM)
How do lipid-soluble and lipid-insoluble molecules cross the cell membrane?
lipid-soluble = diffuse easily through lipid bilayer

lipid-insoluble = diffuse through protein channels called pores
How does water cross the cell membrane?
via protein channels called aquaporins
What is the concentration ratio of K+ inside to outside the cell?
27:1
What is the concentration ratio of Na+ outside to inside the cell?
10:1
What is the dominant salt in extracellular fluid?
NaCl
What is the dominant salt in intracellular fluid?
K+ salts (mostly with phosphate)
Is the H+ concentration higher inside or outside the cell?
inside the cell
What is the most important reason that the cell membrane is negative inside?
the high permeability of the K+ ion channel
What primarily determines the resting membrane potential?
1) the chemical concentration gradients maintained by the Na+-K+ ATPase pump

2) the relative high permeability of the cell membrane to K+
Which way is the chemical flux of K+, into or out of the cell?
out
Which way is the electrical flux of K+, into or out of the cell?
into the cell
Which way is the chemical flux of Na+, into or out of the cell?
into the cell
Which way is the electrical flux of Na+, into or out of the cell?
into the cell
Which way is the chemical flux of Cl-, into or out of the cell?
into the cell
Which way is the electrical flux of Cl-, into or out of the cell?
out
What influences ion conductance?
-the number of ion channels
-the permeability of ion channels
What proteins are embedded in the vesicle membrane of synaptic vesicles?
synaptotagimin and synaptobrevin
Describe exocytosis of neurotransmitters at the axon terminal.
1) Ca2+ enters the axon terminal as a result of an action potential

2) Ca2+ binds to synaptotagimin and a ternary snare complex forms between synaptobrevin of the vesicle and syntaxin and SNAP-25 of the cell membrane, fusing the vesicle to the cell membrane

3) the neurotransmitter is expelled from vesicle

4) ATP is needed to disassemble the ternary snare complex, which will be recycled
What is referred to as a "portable ocean"?
the fluid within the organism (the internal environment) = interstitial fluid
What are the four main body fluid compartments?
1) cells (intracellular)
2) interstitium
3) plasma
4) transcellular
What is the largest fluid compartment of the body?
cells (intracellular)
What is the second largest fluid compartment of the body?
interstitium
What is the third largest fluid compartment of the body?
plasma
What is the smallest fluid compartment of the body?
transcellular
What are examples of lipid-soluble materials that can easily cross the cell membrane?
oxygen, carbon dioxide, ethanol
What forms the boundary of plamsa?
endothelial cells
What forms the boundary of the transcellular fluid compartment?
epithelial cells
Which fluid compartment has the least restrictive/most permeability boundary?
plasma - endothelial cells
Which fluid compartment has the most restrictive/least permeable boundary?
transcellular - epithelial cells
What kind of molecules cross cell membranes?
small, uncharged, lipid-soluble
What kind of molecules cross the epithelium of the transcellular fluid compartment?
lipid-soluble or controlled by the epithelium
What kind of molecules cross the endothelial barrier of the plasma fluid compartment?
allow substances with a MW less than 25,000 MW

(albumin = 69,000 MW)
What is the molecular weight of albumin?
69,000 MW
What are the membrane channels found in epithelial cells?
membrane channels for Na+, Cl-, and H2O
What is the composition of transcellular fluids?
composed of solutes that the epithelial cells secrete into the transcellular space
Where is albumin secreted into the plasma?
the liver
What connects epithelial cells together?
tight junctions
What kind of cells are "polarized," and what does it mean to be polarized?
-epithelial cells

-one side of the cell has different proteins that form channels for solutes than does the other side of the cell
What is the apical side of epithelial cells adjacent to?
the lumen of the transcellular compartment
What is the basolateral side of epithelial cells adjacent to?
the basement membrane of the transcellular compartment (outside of the epithelium)