PSIO 404 Exam 5 Flashcards
Dynorphin
is an “endogenous opiate”
Calcium
can cross the membrane and into the cytoplasm of a cell can bypass a lot of integration and processes right to the generation of cellular responses like muscle contractions or changes in cell shape
Principles of Signal transduction by ion channels
Ion channels exist in allosteric equilibrium between active (open) and inactive (closed) states.
– Inputs for the ion-channel switch favor either the active or the inactive state of the relevant ion channel.
* The resting membrane potential powers ion-channel switches.
*the gate region becomes open and closed
how input signals make a receptor on or off
input -> on = agonist, that is highly specific and non covalent interaction will bind to discriminator domain and the effector domain will have a conformational change to active state to put out output signals
input -> off an antagonist will bind to a different receptor the discriminator domain which will change the effector domain to in inactive conformation leading to no output signals
All ion channels are controlled by
agonists and antagonists
False
on channels can be gated (opened) by:
1. Membrane Potential Δs (for voltage-gated ion channels)*
2. Molecules (for ligand-gated ion channels)**
3. Mechanical force (for mechanosensitive ion channels)
4. Temperature (for temperature-gated ion channels)
*The majority of human ion channels (of the 500 we have).
**Nevertheless, these channels are still the 3rd most
common receptor type used in cell-cell communication.
the three most common types of membrane receptors and the energy supply
- protein kinase coupled receptors = phosphorylation switch
- GPCR = GTPase switch
- ion channel receptors = membrane potential discharge
Resting Membrane potential and ion in signal transduction
outside : K = 100 mV
Na - 20 mV
Cl- = 5 mV
Ca2+ = 0.01 mV
Inside: K+ = 5 mV
Na+ = 140 mV
Cl- = 120 mV
Ca2+ = 1 mV
Describe the common structural features of ion channels.
Cations are Na, K, and Ca
- they have at least 4 subunits that form the central cavity
and contribute to the selectivity filter (K = 2 subunits)
Describe the common structural features of ion channels.
The common structural features of cation channels are
1. selectivity filter, these are formed by p-loops in cation channels and they remove water from ions and permit passage of one or more specific ions
2. central cavity, these are formed by multiple subunits that rehydrate ions that pass into it
3. gate, these are formed by inner helices for many cations channels and are input dirven for opening or closing
Discuss the general structure of prototype 1 and prototype 2 cation channels, and name an example for each type of channel.
prototype 1:
– 6 transmembrane
domains (S1-S6)
– One P-loop between
S5 and S6
-need 4 P-loops to create a selectivity filter
– Where applicable,
S4 is a voltage sensor
Example: (not voltage sensitive InsP3R
prototype 2:
– 2 transmembrane
domains (S5 and S6)
– One P-loop between
S5 and S6
-need 4 P-loops to create a selectivity filter
– For K2P channels,
only need two S5-S6 subunits
are covalently linked for a complete channel
Example:
Kir
Describe voltage gating’s basic theme (basic mechanism).
-Helices 3b and 4 (the “S3-S4 paddle”) are voltage-
sensitive in that they change position, moving
further into the membrane upon depolarization.
-As helices 3b and 4 “swing” upward, the channel is
opened
Briefly describe the structure of voltage-gated Na+ channels.
-propagate action potentials
-have four influx openings and four efflux openings
-are composed of one alpha subunit and three beta subunits
-the alpha subunit forms the channel
-they are gated by the s subunit S4 voltage sensor
-prototype 1
-are inactivated by a separate inactivation domain on the alpha subunit
Briefly describe the function of voltage-gated Na+ channels.
the function of voltage gated sodium channels is to propagate action potentials by traveling the length of the neurons
-voltage gating = > inactivation for a time “(the refractory period) for unidirectional movements of action potentials, once the refractory period passes it is ready for the next AP
Targets:
-local anesthetics such as lidocaine
-neurotoxins like tetrodotoxin (puffer fish), histrionicotoxin, saxitoxin (frog)
Name and very briefly describe the action of two of the four anesthetics or toxins which target the voltage-gated sodium channel.
lidocaine= a local anesthetic
tetrodotoxin= leads to insufficient activation of skeletal muscles which leads to inhibition of contracting muscle to the diagram, paralysis of receptor muscle leading to respiratory arrest and death
histrionicotoxin = used by native tribes on poison arrow
saxitoxin = produced by Gonyaulax catenella is disastrous red tides
they all inhibit the function of of voltage gated sodium channels
Briefly describe the functions of ligand-gated Na+ channels (epithelial Na+ channels, or ENaCs). How do ENaCs act in concert with ion pumps and K+ channels to accomplish their function?
-ENaCs are ligand gated
-some regulate electrolytes balance across epithelia (vasopressin and aldosterone vs. ANP action in the kidney)
-all function in concert with ion pumps and K channels
-some ENaCs are involved in sensation of salty and sweet taste
-Na enters from the environment to the body by entering through an increase in ENaC, sodium will enter in to the cell from the tubular fluid along the collecting ducts, this is accompanied with an increased amount of sodium potassium ATPase and potassium channels so that you can take the sodium that is moving into the cell and cause it to be pumping into the interstitial fluid to be removed
Briefly explain the role of ENaCs in the sensation of taste: in which one or two types of taste do ENaCs play an initiating role?
ENacs are the primary channel involved in salty and sour taste. The signal to the brain with the regulation of electrolytes and water balance if the food is salty or sour
Briefly discuss the structure of voltage-gated K+ channels.
– are highly variable
– have prototype 1 structure w/ four
un-joined, pore-forming a subunits
(homo- and hetero-tetramers)
– are gated by depolarization
– composed of pore-forming a
subunits encoded by >50 genes w/
extensive tissue-specific expression
-each alpha subunit is associated with
a beta subunit which reversibly
plugs pore
Briefly discuss the function of voltage-gated K+ channels.
– function primarily to terminate the
action potential
-important for repolarization
Name and very briefly describe one of the two KV channel blockers mention in lecture.
– KV channels at NMJ synapses are
blocked by dendrotoxins (such as
the venom of the mamba snake)
– Other KV channel blockers
(derivatives of 4-aminopyridine)
are used to treat multiple
sclerosis (MS)
Compare and contrast the function of BK and SK channels.`
-BK channels (Big conductance K+ channels)
– voltage controlled (depolarization), but require an increase in [Ca2+] as well to act (logical AND gates).
– aid in relaxation of smooth muscle
* SK channels (Small conductance K+ channels)
– Gated by Ca2+ alone (not voltage controlled)
– responsible for after-hyperpolarization phase of action potential
Name and very briefly describe one of the two poisons/venoms mentioned in lecture which target BK and SK channels.
- both BK and SK are targets of apamin (component of bee venom) and charybdotoxin (scorpion poison)
-if you block these channels you block repolarization and continued activity of neuron and muscle
Discuss the basic structure and important physiological function of inwardly-rectifying K+ (Kir) channels.
- have prototype 2 structure and open at
negative membrane potentials and close
upon depolarization - set resting membrane potentials and
shape action potentials - Controlled by the ATP/ADP ratio in insulin-secreting cells
1. G-protein-gated inwardly rectifying K+ (GIRK) channels
– are even more signal-regulated
than other types of K+ channels
– gated by Gbg subunits of Gi-proteins
– are the way inhibitory neurotransmitters effect
hyperpolarization in the postsynaptic cell
*how they set the resting membrane potential
Describe the activation (gating) and function of GIRK channels (also known as Kir3 channels).
- G-protein-gated inwardly rectifying K+ (GIRK) channels
– are even more signal-regulated
than other types of K+ channels because they are gated by G proteins (inhibitory G protein)
– gated by Gbg subunits of Gi-proteins
– are the way inhibitory neurotransmitters effect
hyperpolarization in the postsynaptic cell by the beta gamma subunits that interact with these channels leading to a more hyperpolarized cell which means the neuron is less likely to be activated by an action potential and all other cells are suppressed in their polarization status
Briefly describe one of the two examples of the operation of GIRK channels mentioned in class (Hint: both examples are effects of the autonomic nervous system, i.e. sympathetic or parasympathetic effects).
– We’ve seen GIRK effects:
-1.parasympathetic actions on heart,
-with pacemaker cells, activation of the M2 receptor by acetylcholine will lead to activation of the inhibitory G protein that it is coupled too. The alpha subunit that inhibit adenylate cyclase means less cyclic AMP which means less opening of the HCN sodium channel so less sodium can enter the cell. this will reduce the steepness of the pacemaker cell potential. Then the beta gamma subunits bind to the GIRK channels, which the beta/gamma subunit activates the channel and causes it to open, opening of the channel causes potassium to leave, but not enter therefore resulting in more polarized of the cell (hyperpolarization)
-this means the threshold if reach less often in a period of time slowing the heart rate
-2. a2-adrenergic feedback inhibition of NE
release at sympathetic synapses.
– Inhibitory signaling takes two directions:
1. reducing membrane potential via Gbg
and 2. reducing cAMP concentration via Ga
Discuss the structure, function, and critical physiological importance of KATP channels. Specifically, be able to explain how KATP channels enable beta cells of the pancreas to depolarize and thus release insulin when blood glucose levels are high.
– For the KATP channel of pancreatic b-cells, the
ATP/ADP-binding transmembrane protein SUR
(SulfonylUrea Receptor) gates the activity.
– Channel closes when ATP/ADP ratio rises
– SURs are targets of sulfonylureas (anti-diabetes
drugs!
-SUR is activated by the presences of high ATP levels (causing the cell to be more polarized) and is closed with low ATP levels (causing the cell to become more depolarized)
-closed SUR channels - more depolarization of beta cells = release of more insulin
-good diabetes drug
Describe the basic structure and function of K2P channels, and give a couple of examples of how K2P channels are used by our cells.
NOT voltage controlled therefore they are always active and they do not open or close (like background channels)
- Cell sensation of internal mechanical pressure
(osmotic pressure in, ex: a hypotonic solution.)
– To prevent rupture, the cell opens K+ and Cl- channels to move solutes out in an electroneutral way so that cell function is not impaired and osmotic pressure is relieved! Section 14.7.1 in your textbook covers more of this. - Cell sensation of temperature in the hypothalamus.
– These K2P channels close as temperature drops. This leads to depolarization and generation of action potentials. Prostaglandin
E2 & pyrogens also block these channels to increase body temperature. Changed neuron activity mediates proper response. - Cell sensation of disturbance in blood supply to cells.
– Arachidonic acid and lysophospholipids respond to brain oxygen deprivation and prevent fatal accumulation of Ca2+ in brain cells.
Explain how K2P channels are employed by a cell 1) to regulate cell osmolarity, 2) to determine and respond to ↑ body temperature, and 3) to protect against neuron damage in the event of oxygen deprivation in the brain.
- 2P-Domain K+ Channels
– are of prototype 2 structure and are not
voltage-controlled
– also control the resting potential; do not fully
close upon depolarization (they are called
background channels, adjusting resting
membrane potential at different levels)
– are gated by a variety of physical and chemical stimuli
– mechanically-gated for osmotic pressure relief to prevent rupture
– temperature-gated for control of body temperature (these 2P-
channels are in sensory nerves and in the hypothalamus)
– ligand-gated for transmission of pain sensations, protection of
neurons from overstimulation (as in stroke)
– are opened by gaseous narcotics (chloroform, halothane, etc.)
Voltage-operated Ca2+ channels (VOCCs)
IIC. Voltage-operated Ca2+ channels (VOCCs)
* Voltage-operated Ca2+ channels (VOCCs) are
– gated by depolarization and are found in many tissues, in all eukaryotes
* VOCCs connect changes of membrane potential with Ca2+-
dependent cellular processes like secretion & movements.
– VOCCs are critical for neurotransmitter release at synapses, cellular
motility and muscle contraction. The neuron AP’s job is to gate VOCCs
Signal Transduction by Anions
- Primary ion transported is chloride (Cl–), but other ions include
bromide, iodide and nitrate (very low abundance for all of these) - Gating of a Cl– channel can either hyperpolarize (skeletal m. and
neurons) or depolarize (smooth m.) depending upon the
steepness of the concentration gradient of chloride (a
determining factor for the membrane potential value).
Briefly describe the general function of anion channels in the body.
- Primary ion transported is chloride (Cl–), but other ions include bromide, iodide and nitrate (very low abundance for all of these)
- Gating of a Cl– channel can either hyperpolarize (skeletal m. and neurons) or depolarize (smooth m.) depending upon the steepness of the concentration gradient of chloride (a determining factor for the membrane potential value)
Cell sensation of internal mechanical pressure
(osmotic pressure in, ex: a hypotonic solution.)
– To prevent rupture, the cell opens K+ and Cl- channels
to move solutes out in an electroneutral way so that cell function
is not impaired and osmotic pressure is relieved! Section 14.7.1 in
your textbook covers more of this
Cell sensation of temperature in the hypothalamus.
– These K2P channels close as temperature drops. This leads to
depolarization and generation of action potentials. Prostaglandin
E2 & pyrogens also block these channels to increase body
temperature. Changed neuron activity mediates proper response
Cell sensation of disturbance in blood supply to cells.
– Arachidonic acid and lysophospholipids respond to brain oxygen
deprivation and prevent fatal accumulation of Ca2+ in brain cells.
List the 3 families of chloride channels discussed in lecture.
- There are 3 families of Chloride Channels:
1. ClC (Cl– Channel) family
2. CFTR (Cystic Fibrosis Transmembrane conductance
Regulator) family
3. GABA (Gamma-AminoButyric Acid) & Gly receptor anion
channels
- Anion Channels: CFTR (Cystic Fibrosis
Transmembrane conductance Regulator) family
- CFTR governs the
movement of salt
& water across
epithelia - Various toxins
operate by hyper-
phosphorylation of
the regulatory
region
Briefly discuss the structure and function of ClC channels, and be able to give 2 of the 4 specific physiological roles/examples for ClC channels mentioned in lecture.
- composed of 2 subunits to make a single 2-pore channel
- major functions include: control of cell volume and
osmolarity, trans-epithelial electrolyte transport, pH
regulation, acidification for bone resorption, setting the
resting membrane potential, and (mostly-inhibitory)
influences on neurotransmission - a special isoform called
ClC-K is involved with
chloride reabsorption in
the thick ascending limb
of the loop of henle - ClC-K is also important to
endolymph production in
the inner ear - ClC7 is used by
osteoclasts to secrete HCl - other ClCs work with K2P
channels for cellular
osmotic pressure relief
Briefly discuss the structure and function of GABA and glycine receptor anion channels.
- are ligand-gated (GABA and glycine)
– Ligand binding opens the channel and
causes chloride influx (thanks to low
cytosolic Cl− levels) to cause
hyperpolarization - composed of 5 subunits (see righ
List and briefly explain the effects of, two of the five types of agonists for GABA and glycine receptor anion channels given in lecture.
Agonists: alcohol, halothane (also
targets K2P channels), sleep-inducer
barbiturates, benzodiazepines used as
fear reliever
List one of the two industrial chemicals mentioned in lecture which are also antagonists for GABA & glycine receptor anion channels.
- are ligand-gated (GABA and glycine)
– Ligand binding opens the channel and
causes chloride influx (thanks to low
cytosolic Cl− levels) to cause
hyperpolarization - composed of 5 subunits (see right)
- Agonists: alcohol, halothane (also
targets K2P channels), sleep-inducer
barbiturates, benzodiazepines used as
fear relievers - Antagonists: analeptics such as
avermectin (insecticide), picrotoxin
(plant poison) and clinical treatment
for alcohol and barbiturate intoxication
Briefly explain the use of analeptics for the treatment of alcohol or barbiturate intoxication (not addiction, just intoxication).
Agonists: alcohol, halothane (also
targets K2P channels), sleep-inducer
barbiturates, benzodiazepines used as
fear relievers
* Antagonists: analeptics such as
avermectin (insecticide), picrotoxin
(plant poison) and clinical treatment
for alcohol and barbiturate intoxication
output signal can depend on
-pH dependent
-Calcium dependent
-Voltage dependent
signal transduction by cations for sodium channels
- voltage gated Na+ channels
- ENaCas (epithelial Na+ channels)
signal transduction by cations for potassium channels
- Kv voltage gated potassium channels
- Kir inward rectifying potassium channels
- K2p channels
signal transduction by cations for calcium channels
- VOCC voltage operated calcium channels
signal transduction by anions for chloride channels
- CIC (CL- channel) family
- CFTR (cystic fibrosis transmembrane conductance regulator ) family
- GABA (gamma aminoButyric Acid) and Gly receptor and channel
Prototype 1 cation channels can be “gated” by multiple things including voltage, cyclic nucleotides, or InsP3.
True
Which of the following anion channels is used by mucosal epithelia to maintain hydration of mucous membranes?
CFTR channels
Which of the following channels can be assembled on demand based upon the action of G-proteins?
inwardly-rectifying potassium channels
Which of the following is NOT a typical part of cation channels?
a selectivity filter
a pressure relief valve
a gate
a carbohydrate linker for additional specificity
a central cavity
a ligand binding site
-a ligand binding site
a carbohydrate linker for additional specificity
a pressure relief valve
Which of the following is not true regarding the axonal sodium channel?
It is regulated by calcium ions as part of negative-feedback mechanisms.
It assembles in the membrane with a total of 24 transmembrane domains.
It contains a voltage sensor in its S4 transmembrane domain(s).
It has four influx and four efflux openings.
It is regulated by calcium ions as part of negative-feedback mechanisms.
Signal Transduction by Anions
- Primary ion transported is chloride (Cl–), but other ions include
bromide, iodide and nitrate (very low abundance for all of these) - Gating of a Cl– channel can either hyperpolarize (skeletal m. and
neurons) or depolarize (smooth m.) depending upon the
steepness of the concentration gradient of chloride (a
determining factor for the membrane potential value).
To have a noticeable affect on downstream effectors,
the cytosolic [Ca2+] must be between 1-10mM.
How is cytoplasmic Ca generated and maintained
by Ca2+ pumps which operate against steep concentration gradients (with direct
or indirect powering by ATP hydrolysis).
Describe how [Ca2+] differs throughout the cytoplasm vs. within organelles vs. the extracellular space for a typical non-stimulated eukaryotic cell?
outside the cell: typically very high at a concentration of 1 mM
extracellular space (cytoplasm) : typically very low at a concentration of 0.0001 mM
within the organelle : ER = 0.1 - 1 mM
mitochondria = 10 mM
In the cytoplasm of non-stimulated cells, the [Ca2+] is maintained at about 0.1uM. This is a [Ca2+] which is 4 orders of magnitude lower than extracellular [Ca2+] or ER lumenal [Ca2+], ormitochondrial [Ca2+]
- Cytoplasmic [Ca2+] is also 2-4 orders of magnitude lower than [K+], [Na+] and [Cl-], and thus Ca2+ influx rarely changes the membrane potential significantly.
