Slides 3 Flashcards
Where does integration of sensory information typically occur?
Mostly in the pre-frontal cortex
What are the 3 things the brain needs to do in order to produce behaviour?
- Receive info about the world
- Integrate info to create a sensory reality
- Produce commands to control the movement of muscles
What are the brain’s 3 primary functions?
- Create a sensory reality
- Integrate information
- Produce behaviour
How are white matter tracts detected in the brain?
Tractography
Sensory receptors:
specialized cells that transduce (convert) sensory energy (like light) into neural activity
Energy for vision
Light –> chemical
Energy for audition
air pressure –> mechanical
Energy for somatosensation
Mechanical energy and sometimes chemical energy
Energy for taste and olfaction
Chemical molecules
Is our perception an exact replication of the real world?
Not really, it is a subjective construction of reality that is manufactured by the brain
How does the brain distinguish between the different senses?
They are processed in different parts of the brain
Learn to distinguish the senses through experience
Which is our primary sense?
Vision
3 layers of the eye
Cornea: clear outer covering
Lens: focuses light
Retina: where light energy initiates neural activity q
Retina vs Fovea
Retina = light sensitive surface at the back of the eye consisting of neurons and photoreceptor cells Fovea = center of the retina, the receptive field at the senteer of the eye's visual field
what is the function of the bipolar cells?
They connect the rods and cones to the ganglion cells
What cells make up the optic nerve?
The axons of the ganglion cells
Retinohypothalamic tract
Axons of ganglion cells that go to the hypothalamus and contribute to circadian rhythms and pupil size
Characteristics of rods
- More numerous than cones
- Sensitive to dim light
- Used for night vision
- No colour perception
Characteristics of cones
- Responsive to bright light
- Colour and high visual acuity
- Located in the fovea
- Colour vision
2 layers of a photoreceptor
Outer: stacks of membranes that contain visual pigment molecules (rhodopsin)
Inner: organelles and opsin molecules
Geniculostriate visual pathway
Retina –> visual cortex
Main pathway that allows you to form images
Tectopulvinar visual pathway
retina –> superior colliculus
Allows you to detect motions
Visually guided movements
Retinohypothalamic visual pathway
Synapse at the suprachiasmatic nucleus of the hypothalamus
Regulates circadian rhythm and pupillary reflex
Is an image formed at V1?
No, thats where all of the information (colour, motion, depth, form) is integrated
Images are put together in V2, V3, and V4
Dorsal Visual Stream
Occipital –> parietal
How: visually guided movements
Ventral Visual stream
Occipital –> temporal
What: visual identification of objects
Pinna:
Funnel-like external structure of the ear designed to catch sound waves and direct them to ear canal
External ear canal:
Amplifies sound waves and directs them to the eardrum
Middle ear:
An air filled chamber with 3 bones:
- Hammer
- Anvil
- Stirrup
The inner ear has what 3 components?
Cochlea
Basilar membrane
Hair cells
Cochlea:
Fluid filled stricture that have the auditory receptor cells
Basilar membrane:
Receptor surface in the cochlea that transduce sound waves into neural activity
- Where the hair cells are embedded
Hair cells
Sensory cells that when stimulated by waves in the cochlear fluid, push up against the tectorial membrane and make action potentials in the auditory nerve
Fast vs slow wave sound frequencies
Fast: max displacement at base of membrane
Slow: max displacement at apex of membrane
Process of sound wave to NT release
- Sound makes waves in the cochlear fluid which moved the basilar membrane
- Hair cells are anchored in the basilar membrane, so they get pushed up against the tectorial membrane
- Displacement of hair cells changes the membrane potential and leads to NT release
Inner vs outer hair cells
Inner: afferent and make up 90% of auditory nerve
Outer: both efferent and afferent
What direction of movement of the hair cells causes a depolarization?
Movement towards the tallest cilia
K+ entry
Causes Ca+ to enter and NT to be released
What direction of movement causes the hair cells to hyperpolarize?
Movement towards the shortest cilia
Causes less NT release
Where do the inner hair cells synapse to?
spiral ganglion axons that make the auditory nerve (cranial nerve 8)
What brain region helps you detect where sounds are coming from?
Superior Olivary complex
What brain region mediates sound guided movements?
Inferior colliculus
Left vs right temporal lobe in sound processing
Left = language processing Right = spatial dynamics and emotion
Humans have which two types of skin?
Hairy and glabrous
Nociception
Perception of pain, temperature and itch
Hapsis
perception of fine touch and pressure
Identify objects through touch
Proprioception
Perception of the location and movement of the body
- sensitive to the stretch of muscles and tendons and movement of joints
What sense to free nerve endings respond to?
Chemical signals for pain
Rapidly adaptive reception
responds briefly at the beginning and at the end of a stimulus
- touch, fluttering sensations and vibration
Slowly adapting receptor
responds as long as a sensory stimulus is on the body
- pain, temperature, skin indentation
Root ganglion neurons
Axons that carry sensory information from the skin to CNS
- May synapse with other neurons in the spinal cord or go straight to the brain
Proprioceptive and haptic neurons
Large, well myelinated axons –> fast
Ipsilateral in spinal cord and cross at brain stem
Nociceptive neurons
Small, not well myelinated axons –> slow
Cross in brain stem
Primary somatosensory cortex (Broadmans area 3-1-2)
Receives projections from the thalamus
Begins the process to constructing perceptions from somatosensory information
Secondary somatosensory cortex
Brodman’s area 5 and 7
Refines the construction of perceptions
Projects to the frontal cortex
Integrating vision with somatosenses
The dorsal stream projects to the secondary somatosensory cortex and then to the frontal lobe
Movement planning in the frontal lobe
Prefrontal: planning movements
Premotor: organizes motor sequences
Primary motor: produces specific movements
Axon projections of one eye
Half stay on the ipsilateral side and go to the contralateral side
Which receptors are furthest away from the lens?
Photoreceptors
What cells are the interneurons of the visual system?
Amacrine and horizontal cells
Which cells does light reach first in the eye?
Ganglion cells
Which eye cells produce action potentials?
Ganglion and amarine cells
What eye cells produce graded potential
Photoreceptors, horizontal cells and bipolar cells
What NT do photoreceptors release?
Glutamate
How are pigments arranged in rods and cones?
Rods: in disks that do not contact the membrane
Cones: comb-like structures that are continuous with the membrane
How many disks are replaced each hour?
3, it requires a lot of energy
What is rhodopsin made of?
A complex of a large opsin protein and a light absorbing retinal
What does the opsin protein look like?
A large protein with 7 hydrophobic trans-membrane helices
What happens to retinal when it absorbs light?
It changes shape = photoisomerization
It goes from 11-cis retinal to all trans retianl
What happens to rhodopsin when retinal changes shape?
The whole protein changes shape
What molecule is crucial for phototransduction?
Metarhodopin II
All-trans retinal is the precursor for what?
11-cis retinal
What nutrient is needed from our diet to make all-trans retinal
Vitamin A
What is the confirmation of retinal at rest>
11-cis retinal
Because all-trans retinal is more straightened out, what happens to the rhodopsin protein when activated by light
The opsin gets pushed open
What is different between photoreceptors that capture different colour wave lengths
the amino acid sequences are slightly different
How do invertebrates’ photoreceptors respond to light?
Depolarization
How to photoreceptors in vertebrates respond to light?
Hyperpolarization
What does photoactivated rhodopsin (meta II) do when stimulated?
It activates the G-protein transducin, initiating the phototransduction cascade
What is the activity of photoreceptors in the dark?
Na+ and Ca++ enter ion channels and cause depolarization and glutamate is released
What happens to the activity of the photoreceptor when stimulated by light?
The sodium channels close due to reduced levels of cGMP
Rod becomes hyperpolarized and reduces glutamate release
Levels of cGMP and sodium channels
High = channel open Low = channel closed
The g-protein transducin has 3 subunits. What happens to the alpha subunit during transduction?
Alpha exchanges GDP for GTP
It break off and activates the membrane bound phosphodiesterase. It hydrolyzes cGMP to GMP –> reducing levels of cGMP
What happens when there is decreased cGMP?
It is less able to bind to Na channels, so they close and the rod hyperpolarizes
What dictates the specific wave length that will stimulate a rod?
The amino acid sequence of the opsin molecule
The amount of of NT released from the rods is related to what?
The amount of light
Is there a blood brain barrier on the nose?
No
Sequence of olfactory cells
Receptors to Glomerulus to Mitral cells (which make up the olfactory projection)
What are the inhibitory cells in olfaction
Periglomerular cells (connest the glomerulus together)
Tufted cells
Granule cells
Odour applied to the soma makes what type of response?
A short rapid response
Odour applies to the dendrites of cilia produce what type of response
A large, long lasting response
|»_space; Due to second messengers
What receptors are involved in smell and where are they located?
Golf receptors
In the cilia
What happens to the Golf receptor when an odour binds?
- Alpha subunit dissociates
2a. Activates adenylyl cyclase and increases cAMP
3a. Opens Na and Ca channels influx
2b. Also a activates phospholipase 3
3b. Converts PIP2 to IP3
4b. Opens Ca channels
What happens when the olfactory cilia become depolarized (influx of Na and Ca)
Ca causes the chloride channels to open, and Cl effluxes, causing further depolarization
What happens when the olfactory cilia become depolarized (influx of Na and Ca)
Ca causes the calcium-activated chloride channels to open, and Cl effluxes, causing further depolarization
What does it mean to say that odour receptors are more general?
More than one odourant type can bind to each receptor
Why do odour receptors need to be constantly replenished?
Because they are constantly being killed off, maybe from all the calcium
Are receptor types evenly spaced in the nose/
No, particular odourant receptors are found in restricted areas of the olfactory epithelium
Where do olfactory receptors project to?
To the olfactory bulb
Which mainly projects to the amygdala
What is the significance of lots of olfactory projections to the amygdala
It makes unconscious emotional assessment of odour
What other sense enhances taste?
Smell
Which flavours have g-protein receptors?
Umami
Salty
Bitter
Sweet
Where are taste buds located?
Mainly within small bumps on the tongue called papillae
But they are all throughout the mouth
Do taste cells have axons?
No, they form chemical synapses with afferent neurites
What is the signal transduction pathway for all G-coupled taste receptors
- Alpha subunit activate phospholipase 3
- Phospholipase 3 make PIP2 into IP3 and DAG
- IP3 release calcium from ER 4. Increased calcium levels make NT release
What is the scala media?
It is the fluid in the cochlea that has a high concentration of potassium and low concentration of sodium that the hair cells are in
Fast waves = ______ pitch
High pitch/frequency
The scala media has a high concentration of K and low Na, so what ion rushes in when the hair cell channels open?
Potassium
After K rushes into the hair cell, what happens?
There is a calcium influx which causes NT release
What is another name for the hair cells?
Stereocilium
What connects the stereocilium?
Tip links - a coiled protein
How do the tip links open ion channels on hair cells?
When the hair cells move, they tension in the tip links increase and this promotes the opening of K channels
What protein opens the gates of the ion channels when there is tension in the coil between hair cells
myosin
How do hair cells adapt to sound?
The myosin protein slides down the kinocilium, which reduces tension in the coil and closes the gates
What type of calcium channel is in hair cells?
Potassium gated calcium channel
What important function does calcium play in hair cells?
Stimulates the release of NT
How are nocioceptive, hapsis, and proprioceptive receptors stimulated?
Nociception : free nerve endings activated by chemicals
Hapsis : activated by mechanical stimulation of the hair or tissue
Proprioception: sensitive to stretch and tension of muscles
Rapidly adapting receptor
responds breifly to the beginning and the end of a stimulus on the body
Slowly adapting receptor
responds as long as sensory stimulus in on the body
Stretch receptor (weak vs strong)
sense the stretch of the muscle
Weak: produces grated potential
Strong: produces action potential
Fast vs Slow adapting stretch receptor
Slow adapting = persisting firing
Fast adapting = declining firing
What is the muscle spindle made of?
small intrafusal fibers that are embedded in the bulk of the muscle
What two types of neurons innervate the muscle spindle?
- Large muscle fibers are supplied by alpha-motorneurons
2. Intrafusal fibers are supplied by gamma efferent fibers
Group 1A of the afferent neurons of the muscle spindles
Large diameter, fast conducting that from the primary nerve ending
Group 2 of the afferent neurons of the muscle spindles
Smaller and conduct more slowly, that form the secondary nerve endings
Primary nerve endings of the muscle spindle
Sensitive to the rate of change of the stretch (rapidly adapting)
> connected to group 1A axons
Secondary nerve endings of the muscle spindle
Sensitive to the level of static tension (slow adapting)
> connected to the smaller group 2 axons
What are 3 ways that mechanoreceptor channels can be opened?
- Through forces conveyed through tension in the membrane
- Forces affecting coiled proteins linked to the channel gate
- Indirectly activated by a second messenger
What ion enters the muscle when it contracts
Sodium
What are the two main receptors involved in pain perception?
G protein coupled receptors (GPRC) - metabotropic
Transient receptor potential (TRP) - ionotropic
TRPs have different thermal activation ranges, what does that mean?
Different chemicals produce sensations of temperature that are not necessarily painful (menthol)
How do GPCR affect TRP?
The activation of GPCR can increase the sensitivity of TRPs
GPCR - TRP axis
When the GPCR and stimulated, they can lead to the activation of different kinases which phosphorylate the TRP and activate them –> TRP gets sensitized to pain
What is the mechanism of the GPCR - TRP axis
- GPRC stimulates phospholipase C (PLC)
2 PLC stimulates PKC
3 PKC activated TRP
There are many different mechanisms, but the important component is that a Kinase phosphorylates TRP
What part of the spinal cord are the pain receptors located?
Dorsal horn
What can make nociceptors hyper-reactive
- more transducers
- more GPCR
- more signalling
- more Na channels
What role does inflammation play in pain sensitivity
Inflammation can phosphorylate TRPs and alter the thresholds of activation
What causes the delay between stimulation of a pre-synaptic neuron and a post synaptic response?
The time it takes the NT to travel across the cleft
What causes the delay to increase and decrease
Temperature
Warmer = less delay
What is required for an action potential to occur?
A depolarization of the cell
Do depolarizations always result in action potentials?
No
but action potentials are the strongest depolarization
What causes the delay between the end of an action potential and the release of NT?
- The time required to open calcium channels
2. The time it takes Ca entry to trigger NT release
Depolarization leads to the increase of what ion in the cell?
Calcium
High levels of Ca trigger the release of NT. Where are Ca channels mostly located?
Concentrated in the active zones of the terminal membrane
In terms of the active zone and calcium channels, what increased the chance that NT will be released
If there is a bigger active zone with more calcium channels
What is the readily releasable pool?
The collection of vesicles that are bound to the pre-synaptic membrane at the active zone that are able to be rapidly released
What is the reserve pool?
Vesicles in the middle of the terminal button that are bound to each other by actin filaments that are ready to be put into the readily releasable poo;
What is the quantum of transmitter?
The amount of NT contained in one vesicle = there is a set number of NT per vesicle
What are the names of the 3 steps of vesicle NT release?
- Docking
- Priming
- Exocytosis
What does HVA stand for in terms of calcium channels?
High voltage activated
Which subunit in calcium channels forms the pore?
The alpha-1B subunit
Which subunit in calcium channels forms the pore?
The alpha subunit
Which type of calcium channel do we focus on in this course?
N-type
What is the composition of the calcium channel protein?
Alpha in the middle, flanked by beta and gamma subunits
- beta in intracellular
- gamma has 4 transmambrane segments
- alpha2 is extracellular
Is there just one type of each subunit in the calcium pore?
No, there are many different isoforms
In calcium channels, the alpha subunit is the largest, and it incorporates (4):
- Conduction pore
- Voltage sensors
- Gating apparatus
- Ligand binding sites
How many segments are there in the alpha subunit of the calcium channel? What do they do
6
S1-S4 are the voltage sensor molecules
S5&6 form the pore
How does the calcium channel open?
As the S5 and S6 subunits are activated, they twist and open the pore
What are the 3 different stages of voltage gated ion channels?
Activation = pore open Deactivation = pore closed Inactivation = pore closed and unable to open
There are two types of SNARE proteins embedded in membranes that form a complex:
V(esicle) SNARE
T(plasma membrane) SNARE
What is the name of the v-SNARE?
Synaptobrevin
What are the names of the two t-SNAREs
SNAP-25
Syntaxin-1
What is the function of synaptotagmin?
A Ca binding protein in the synaptic vesicle membrane
What happens to synaptotagmin when there is a calcium influx due to a depolarization?
Calcium will bind to synaptotagmin and will change the conformation from a trans to a cis state
What happens when synaptotagmin goes from a trans to a cis state?
It binds to the plasma membrane and pulls the vesicle closer to it, which allows it to dock and fuse
Primed vs non-primed excitosome
Primed: a docked vesicle-SNARE complex that is ready to be released
Non-Primed: a docked vesicle-SNARE complex that is not ready to be released because it is not close enough to the membrane
What does the non-primed excitosome complex unit consist of?
- A calcium channel
- Syntaxin 1
- SNAP 25
- trans synaptotagmin
What keeps the non-primed complex away from the membrane?
The electrostatic repulsion of the negative charge of trans synaptotagmin
What happens to the non-primed complex when there is a depolarization?
Ca concentration increases and binds to synaptotagmin which inserts itself into the membrane
Once the excitosome is primed, it is ready for what?
Fusion
What is the process of fusion?
Calcium binds to synaptotagmin which binds to the SNARE complex. Complexin leaves and an omega figure is formed
In the docking phase, what protein is holding syntaxin in its native conformation?
Munc
The SNARE complex that is formed by the tangling of synaptobrevin, syntaxin and SNAP 25 is stabilized by what during priming?
A protein called complexin
Once the NT are released, the synaptic vesicle is recycled by ______
Endocytosis = a bubble comes off the plasma membrane
Neurotransmitter release is regulated by what two things?
- Rate of neuron firing
2. Probability that vessicles will undergo exocytosis
What NT is used in all neuromuscular synapses?
Acetylcholine
What other synapse is ACh used in?
Parasympathetic terminals
How is the precursor to ACh, Acetyl CoA made?
During glycolysis when pyruvate is broken down, acetyl groups are transferred to the coenzyme A
Where does choline come from?
Our diets
What are the two components that make up ACh?
Acetyl CoA and Choline
How are Acetyl CoA and Choline combined to make ACh?
the enzyme Choline Acetyltransferase
What puts NT into vessicles and what else does it determine?
Vesicular Neurotransmitter Transporters
they determine how many NT are in each vesicle
What energy source drives the vesicular neurotransmitter transporters?
the proton electrochemical driving force gradient
What happens to the concentration of receptors as you move away from the post-synaptic density?
There are fewer receptors
How many subunits are in the nicotinic ACh receptor?
5 subunits around a central pore
Which subunit has the binding site in ACh receptors
Alpha
How many alpha subunits are there in ACH receptors?
At least 2 `
What ion rushes in when ACh receptors open?
Sodium
Different subunit combinations of the ACh receptor dictate what?
The different functional properties of that receptor
How many trans membrane domanes does each subunit have in the ACh receptor and what are they labeled?
4
M1-M4
In which ACh subunit domain is the binding site located?
The larger M1 amino terminal domain
What does the ACh M2 domain do?
determines the ionic selectivity of the receptor and faces the inside of the channel pore
What is the secondary structure of the ACh subunits that span the membrane?
Non-polar (hydrophobic) alpha helixes
Where specifically on the ACh receptor does ACh bind?
To the cys-loops on the beta pleated sheets on the extracellular side
What happens to the ACh receptor when ACh binds?
- The beta sheets rotate
- This causes M2 to move outward
- This opens the pore
What is the precursor molecule to GABA?
Glutamate
What are the two main Glutamate receptors?
AMPA and NMDA
How do the AMPA and NMDA receptors work together?
When AMPA is stimulated it lets sodium in.
The sodium will activate NMDA and calcium will enter
How many subunits are there in the AMPA receptors and what are they called?
4
GluA1 to GluA4 (or Glur1-4 or GluR-A - D)
Each AMPA subunit can exist in what two forms? Caused by what?
“Flip” and “flop”
Caused by alternative splicing
What is different about the flop GluA2-GluA4 AMPA subunits?
They desensitize faster but recover slower
AMPA receptors usually only allow sodium to flow in, but in what case does to allow Calcium in as well?
If the GluA2 receptor is (Q) instead of (R)
> (R) is due to a post-transcriptional modification
Is GluA2 (R) or (Q) caused by a modification?
(R)
How many subunits in the GABA receptor?
5
GABA binds to which sub unit and how many of these subunits are there?
Alpha
There are 2
When the GABA pore is open, which ion rushes in?
Chloride
Barbituates, ethanol etc have their ___ binding sites on the GABA receptor
Own
What is the function of tonic inhibition?
It is baseline inhibition that makes sure there is not random excess excitation
Desensitization of the GABA receptor
Even when GABA is bound the pore will not open, it is in a constant in between state
> caused by over use (alcoholism)
What is the difference between the GABA(A) receptor and the GABA(B) receptor?
GABA(A): direct acting - has a pore
GABA(B): indirect acting - opens a channel through second messengers
What receptors are direct acting and which are indirect acting
Direct = ionotropic Indirect = metabotropic
What are the 4 main G-proteins?
Gs
Gq
Gi
Go
What is the effector of the Gs protein?
More adenylyl cyclase –> more cAMP –> more PKA
What is the effector of the Gq protein?
More PLC –> IP3 –> Ca Diacylglycerol –> PKC
What is the effector of the Gi protein?
Less adelylyl cyclase –> less cAMP –> more K channels open –> inhibition
What is the effector of Go protein?
less Ca channels shut –> less NT release
What is the composition of G-protein coupled receptors
7 transmembrane domains
Extracellular amino terminals
Intracellular carboxy terminals
Which intracellular loops are the binding cites?
2nd and 3rd
What can lead to the desensitization of the G-protein?
Phosphorylation
Which domains do ligands bind to in G-proteins?
TM3,5,6,7
What happens when a ligand binds to the G-protein?
The subunits twist and the alpha and beta/gamma subunits break off
When the G-protein is stimulated, what happens to the alpha subunit?
It exchanges GTP for GDP and the alpha subunits becomes activated
What on the receptor determines what G-protein configuration will bind?
C-terminus
Once the alpha and beta/gamma subunits are freed from the G-protein, what do they do?
They modulate the activity of target proteins
What protein turns GTP back into GDP
GTPase-activating proteins
Once GTP is turned back into GDP, what can happen?
The trimer can reassemble and attach back to the G-protein
Is the beta/gamma subunit complex membrane bound?
yes
What does the G-protein beta/gamma subunit do once activated?
It can interact directly with an ion channel to open or close it
What does the G-protein alpha subunit do once activated?
It can activate one or more enzymes that can alter ion channel activity through second messengers
How to the Gi beta/gamma subunit open a potassium channel?
Directly
Induces a post-synaptic hyperpolarization
How do the Gi beta/gamma subunits open channels
Possibly by causing a rotation in the sub units
Which NT can bind to autoreceptors?
Norepinephrine
What happens what Go protein autorecepots are stimulated?
It causes the a,b,g subunits to release and bund to N-type calcium channels, inhibiting calcium influx and reducing NT release
Gs pathway
Alpha subunit is activated –> activates adenylyl cyclase –> turns ATP into cAMP –> activates PKA –> phosphorylates CREB –> initiates transcription
What does the Gq protein do when stimulated?
Phospholipase C –> turn PIP2 into IP3 –> Activate ER to release Ca++ –> Ca++ does many things
Why does intracellular calcium need to be very well regulates?
Because it is very cytotoxic
A neuron can make how many connections?
50 000
EPSPs are associated with the opening of what channels?
Sodium: influx
IPSPs are associates with the opening of what channels?
Potassium: efflux
Chloride: influx
Within the plane of the membrane, what forms a selective filter for cations/anions?
Negative and positive charges
What is the main difference between sodium and potassium channels?
the 4 subunits of the sodium channel are all linked up
the 4 subunits of the potassium channel are all separate
In a voltage gated sodium channel, there are __ domains each with ___ transmembrane segments
4
6 (S1-S6)
Which segment in the voltage gated sodium channel is responsible for voltage sensing?
S4
Which segments in the voltage gated sodium channel form the pore that ions flow through?
S5 and S6
In a voltage gated potassium channel, there are __ domains each with ___ transmembrane segments
4
6
How many subunits form the pore in a voltage gated potassium channel?Expressed with accessory ___ subunits
4
Beta
What makes the sodium channels selective
the ring of 4 glutamic acids that line the insides of the pore
What makes the potassium channels selective?
backbone carbonyl oxygens
How many binding sites are there within the potassium pore and what binds to the,?
4 (s1-s4)
Two water molecules and two potassium molecules
Potassium channels are often ____ at rest
open
Sodium channels are often ____ at rest
closed
How do the voltage gated potassium channels open once stimulated?
It causes a rotation of the S4 domain, which intereacts with S6 segments to open the gate