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Neurobiology > Exam III > Flashcards

Exam III Flashcards

1
Q

2 broad categories of senses

A
  1. Special senses - HSTV hearing, smell, taste, vision

2. Somatic senses - TTPP touch, temp, pain, proprioception

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2
Q

What is sound?

A

Vibration of air

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3
Q

What is light

A

EM waves

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4
Q

Process of signal transduction

A
  1. Stimulus comes in form of energy
  2. Sensory potentials
  3. APs
  4. Brain interpretation
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5
Q

Signal transduction pathway

A
  1. Stimulus activates sensory Rs
  2. Sensory Rs act as signal transducers
  3. These primary sensory neurons project into CNS, and connect to 2° sensory neurons
  4. Which then project to various cortical regions
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6
Q

If APs are more or less the same, how does our brain perceive a particular stimulus?

A
  1. Location of stimulus
  2. Type of Rs activates

–> tell the brain what the signal is

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7
Q

3 types of stimuli

A
  1. Mechanical (touch, hearing, temp, noxious)
  2. Electromagnetic
  3. Chemical (smell, taste)
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8
Q

What do sensory Rs do?

A

Signal transducers

Convert energy stimuli into electrical signals – receptor potentials – and when large enough, trigger AP

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9
Q

Stimulus has 4 attributes that the brain can register

A

MILT

  1. Modality (quality) - depends on physical-chemical energy
  2. Intensity - coded by # of Rs activated
  3. Location - topography, vision field, hair displacement/act
  4. Timing - speed + duration
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10
Q

To encode modality…

A

Stimulus must be

  • adequate
  • threshold
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11
Q

PhotoRs

A

4 different photoRs

Activated by light at different wavelengths

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12
Q

Hair cells

A

Found in cochlea

Have different sensitivities based on location

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13
Q

Encoding of intensity

A 
# of Rs
AP frequency
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14
Q

Encoding of location

A

What part touched, vision field, hair cells activated

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15
Q

Encoding of timing

A
  1. Tonic Rs - slowly adapting

2. Phasic Rs - fast-adapting

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16
Q

Where does phototransduction take place?

A

Retina

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17
Q

Steps of vision

A
  1. [PHYSICAL] Light –> eye –> focused on the retina
  2. [PHOTOTRANSDUCTION]
  3. Processing of visual info by retina and brain
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18
Q

Eye anatomy

A

Retina detects light (back of eye)
PhotoRs located on retina
Lens on front focuses light to retina, iris can contract/dilate to let less/more light in

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19
Q

Retina

A

Back of eye

Has photoRs - primary efferent ganglion cells

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20
Q

2 types of photoreceptors

A

Rods - low light, no color - on edge

Cones - higher light, color, spatial acuity - in center

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21
Q

Retina has how many types of…

A

4 types of photoRs

  • 1 type of rod, 3 types of cones (respond to diff λ)
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22
Q

Rods and cones can be divided into 3 components

A
  1. Outer segment - light sensitive part; many disks that contain photopigment (invaginations of PM in cone, pinched off in rods)
  2. Inner segment (contains nucleus and cells)
  3. Synaptic terminals (contain NTs, release GLUT; project to bipolar cells, which express various types of GLUT Rs, can dep./hyp)
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23
Q

Rods and cones have what type of potentials?

A

Only R potentials, cannot fire AP

Directly release NTs

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24
Q

Rods v. cones

A
  1. Many more rods (20:1)
  2. Rods have more photopigment, more disks
  3. Rods have higher convergence
    (many rods converge onto bipolar cell)
    (cones almost always make 1:1:1 connections)
  4. Rods more sensitive to light
  5. Rods have low acuity
  6. Rods = no color (mono), cones = color
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25
Q

Rod v. cone current

A

Rod current responds and decays slowly

Cone = fast response, fast decay

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26
Q

Light produces current via

A
  1. Biochemical pathway leads to ↓ in cGMP

2. Closure of cGMP-gated channels

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27
Q

Cone RMP

A

-40mV

Light hyperpolarizes cell at increasing intensities

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28
Q

Why do cone cells have an RMP so much less negative than other?

A

RMP normally set by leakage of K+ channels
-40 far away from that
Other channels must be open in the dark

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29
Q

Phototransduction in retina process

A

Within the membrane of disks…

  • there are rhodopsins (they are photopigments – they are GCPRs with a light-sensitive mol covalently attached to it)
  • Rhodopsin is coupled to a G protein called Transducin
  • Transducin activates enzyme PDE, which breaks down cGMP
  • cGMP binds to CNG channels (nonselective cation channels that conduct Na+/Ca into cell on outer PM)
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30
Q

What is the “dark current”?

A

In the dark, [cGMP] in cytoplasm is HIGH

  • cGMP binds to CNG channels, activating/opening them
    bc these channels are continuously open, RMP is much less neg (↑ Na+/Ca2+), at -40 mV

In inner segment, there is K+ channel taking K+ out (not sensitive to light) which helps to balance

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31
Q

CNG channels

A

Present in membrane outer segment

Conduct Na+/Ca into cell

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32
Q

What is the lumen of the disk like?

A

More/less like extracellular environment

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33
Q

What happens when light is shined?

A

Rhodopsin –> Transducin –> PDE –> Breakdown/↓ in cGMP –> channels begin to close –> hyperpolarization
….dark current abolished by light

Within disks (outer segment of rods/cones)...
Rhodopsins (photopigments, GCPRs with light-sensitive mol covalently attached) --> coupled to a G protein called Transducin --> Transducin activates enzyme PDE, which breaks down cGMP --> cGMP unable to bind to/activate Na+/Ca channels, making the cell more neg (hyper.)
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34
Q

What does cGMP do in phototransduction pathway?

A

cGMP binds to CNG channels (nonselective cation channels that conduct Na+/Ca into cell)

Located on PM of outer segment in rods/cones within retina

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35
Q

When dark current is abolished, what channels are open/closed?

A

CNG channels (which conduct Na+/Ca into cell) are closed due to ↓ in cGMP

K+ channels on inner segment is still conducting K+ out, which will reduce MP to a neg level

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36
Q

Rhodopsin

A

Photopigments – they are GCPRs with a light-sensitive mol covalently attached to it

2 parts:
- opsin (GCPR)
- 11-cis-retinal
cis configuration in dark (inactive)
trans configuration in light (active)

Δ in retinal from cis->trans –> confirmation Δ of opsin –> which allows it to activate transducin

Retinol recycled

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37
Q

What happens if there’s a mutation in the CNG channel?

A

W/o channels, there’s no phototransduction

Responsible for light –> electrical signal

NT-release in phototransduction dependent on Ca2+, which CNG channels bring into the cell

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38
Q

NT-release in phototransduction

A

Dependent on Ca2+

NTs continuously released in the dark

Different Rs will interpret the NT as hyper./dep.

NT type????? GLUT?

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39
Q

Amplification in phototransduction

A

OP
Bc light activates a biochemical cascade, there’s a lot of amp

*OPSIN can activate 800 g-proteins
g-protein activates PDE 1:1
*PDE can hydrolyze 6 GMP molecules

Absorption of 1 photon ~200 CNG channels

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40
Q

What is mainly responsible for dark current?

A

CNG channels mainly conduct Na+
(mainly responsible for dark current)

A little bit of Ca gets in too

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41
Q

What does Ca2+ do in phototransduction

A

Slightly contributes to dark current through CNG channels (although mostly Na does this)

In dark, a little Ca gets into cell through CNG

  1. Ca reduces sensitivity of CNG channels to cGMP
    ….since cGMP opens CNG channels…now less Na/Ca+ is getting into cell
  2. Ca inhibits the enzyme guanylatecyclase (which turns GTP -> GMP)
    ….less Na/Ca+, less dark current
  3. Ca inhibits rhodopsin kinase (which P rhodopsin)
    …inactivates light cascade

Turn on light…

Light will close CNG channels, meaning no Ca/Na influx

- ↑ in cGMP (bc Ca not blocking guanylatecyclase (GTP -> GMP)
 - ↑ in CNG sensitivity to cGMP

=> REDUCED SENSITIVITY TO LIGHT! due to ↑ cGMP, ↓ rhodopsin activity

Allows cells to react increasingly to light

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42
Q

How do we see color?

A

We see color bc we have 3 different types of cones

which are activated by 3 different wavelengths of light

  • each cone has a different tuning curve for light
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43
Q

How do cones respond to various wavelengths of light?

A

B, G, and R cones…

Have different types of opsins

  Retinol same, opsins different

(Different opsin AA sequences)

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44
Q

Obsins AA comparison

A

Red and green obsins = highly similar

just a handful of different AAs

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45
Q

Role of AAs in photopigments

A

Make photopigments respond to green v. red v. blue light

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46
Q

Distribution of red, blue and green cones in retina

A

Mostly red and green

Only 5-10% blue

Red/green ratio vary, but does not affect color perception

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47
Q

Causes of color blindness

A
  1. Lacking 1+ types of cones
    -> caused either by
    degeneration of cones
    CNG channel mutation
  2. Mutation in cone photopigments
    shifts tuning curve –> partial/total colorblindess
  3. Damage to visual cortex
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48
Q

Mutations of CNG channels

A

Causes partial or total color blindness

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49
Q

NT release reduction in vision

A

Reduction of dark current and continuous efflux causes mem. hyperpolarization

—> Reducing GLUT release

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50
Q

What reversal potential does Na+ give you

A

+60 mv

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51
Q

What reversal potential does Ca2+ give you

A

+60 mv

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52
Q

Which molecules can give you rev potential of +60 mv?

A

Na+ and Ca2+

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53
Q

What is hearing?

A

Perception of sound energy

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54
Q

What is sound?

A

Compression/decompression of air

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55
Q

What does a tuning fork do?

A

Causes vibration of air

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56
Q

3 properties of sound

A
  1. Pitch/tone: determined by frequency*
  2. Intensity/loudness: measured in dB
  3. Timbre/quality: based on overtones
  • frequency: how many waves per 1 second (Hz)
    ex: 5 waves per 1 sec = 5 Hz
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57
Q

What is frequency (in regard to sound)?

A
  • frequency: how many waves per 1 secondunit - Hz
    ex: 5 waves per 1 sec = 5 Hz
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58
Q

What happens to our hearing ability as we age?

A

We lose ability to hear very low and very high frequencies

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59
Q

How are dB measured?

A

Log form

We can perceive a very large range of sound intensity/loudness, so we put it in log

Normal convo: 60 db (1m x higher than threshold)
Rock concert: 120 db (1 tril x higher than threshold)

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60
Q

What do very high sounds do?

A

Damage hair cells responsible for transduction

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61
Q

What does outer ear do?

A

Outer: sound conduction

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62
Q

Sound vibration traveling - sound transduction

A

Ear vibration –> tympanic mem vibration –> 3 bones vibration –> pushes on oval window –> vibration transmits waves of sound into the cochlear fluid –> fluid vibration causes movement of tectoral+basilar membrane –> bending of hair cells causes transduction

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63
Q

Ear anatomy

A

Outer ear –> tympanic membrane –> 3 bones of middle ear –> oval window –> cochlea

Sound mechotransduction occurs in the cochlea

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64
Q

Steps in sound mechanotransduction

A

(1) air wave → (2) mechanical vibration of the ear bones → (3) fluid vibration in the cochlea→ (4) movement between tectorial and Basilar membranes → (5) RP in IHCs → (6) release of NT from IHCs→ (7) AP firing in the auditory nerve

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65
Q

Cochlea structure

A

Has 3 fluid-filled compartments

  1. Vestibular duct
  2. Cochlear duct
  3. Tympanic duct
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66
Q

Cochlear duct

A

Middle fluid filled

Contains endolymph (fluid that is similar to cyto, high in K+)

~140mm [K+]

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67
Q

Vestibular duct

A

Top fluid filled

Contains perilymph (fluid that is similar to extracell/IF,
high in Na+)

140 mm Na - High
2 mm Ca - Normal
10 mm K - Low

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68
Q

Organ of Corti

A

Sensitive element in the inner ear and can be thought of as the body’s microphone

In b/w tectoral and basilar membrane

4 rows of hair cells protrude
3 rows OHC, 1 row IHC

OHC: finetune responses of IHC, sharpen frequency
IHC: signal transduction/turn vibration into sound

these hair cells' bodies are anchored on basilar mem

IHCs make synaptic connections with auditory nerves and release NTs that go to brain

OHCs innervated by efferent nerves (outward innervation)

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69
Q

Inner hair cell bundles

A

Consists of 2 types of cilia

  1. kinocilia (only 1 per bundle)
  2. stereocilia (20-50 per bundle)

Cilia embedded in tectoral membrane, particularly the taller ones

Kinos tall, stereos shorter

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70
Q

Hair cells on bm

A

Close to oval window: respond to high frequencies

Close to cochlear apex/end: respond to low freq

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71
Q

Endocochlear potential

A

In IHCs…

Hair bundles immersed in endolymph
Basolateral side immersed in perilymph

Large voltage difference
+ 80 mv in endo
0 in peri (ref point)
-50 in IHC cyto

Meaning endolymph much more positive

This is the endocochlear potential

  • Inside of IHC is negative
    large voltage difference b/w endolymph and IHC cyto

Tight junctions prevent exchange of ions b/w
endo/IHC extracell./paralymph (sealed up)
in b/w hair cells and other cells

IHCs release NTs - cause R potentials
glutamate binds to ionotropic Rs in afferent nerve endings

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72
Q

How does bending of IHCs produce R potential?

A

Bundles the stereocilia are often lined up in rows of increasing height, similar to a staircase

Tiny springs, called tip links, connect the tips of stereocilia
run upward from shortest to tallest
streched when pushed from short->long

When stretched (pos), they open ion channels that are located on tip of stereocilia 
 - these nonselective cation channels conduct K+

Even though [K+] is same in endolymph and IHC cyto, due to very large voltage difference (+80 in endo, -50 mV in IHC cyto) =====> this creates a very large driving force

      --- > K+ pushed in endo->cyto
causes depolarization

When hair bundles pushed other way (neg), channels close, causes hyperpolarization (some ~15% channels open at rest)

73
Q

Voltage/[ ] differences surrounding IHCs

A

Endolymph (fluid that is similar to cyto, high in K+)
~140mm [K+]
+80 mV

Perilymph (fluid that is similar to extracell/IF, high in Na+)
    140 mm Na - High
    2 mm Ca  - Normal
    10 mm K  - Low
0 mV

IHC cyto
~140/5mm [K+]
-50 mV

Large voltage difference
+ 80 mv in endo
0 in peri (ref point)
-50 in IHC cyto

74
Q

IHC bending response

A
  1. Highly sensitive
  2. 3 nm (diam of K+ ion) enough stretch to open/close channels
  3. Extremely fast
    direct, can open in 10 μs
75
Q

Tip links - function and structure

A

Tiny springs that connect tips of stereocilia

Run upward from shortest to tallest (L->R)
streched when pushed from short->long

Tip links made of protein
Ca+ important for integrity
Ca+ chelators destroy tip links and destroy sound transduction

Each tip link has ~100 ion channels

Composed of at least 2 proteins
bundle together to form dimer, dimers bundle together to form tip link
Cadherin21 and Protocadherin15

76
Q

What are tip links composed of?

A

Cadherin21 and Protocadherin15

77
Q

What are the channels in tip links?

A

TCM1 is the mechanotransduction channel

found in IHCs
has 10 transmem segments
believed to be a dimer with pore

nonselective cation channel, conducts K+ into IHC

78
Q

TCM1

A

TCM1 is the mechanotransduction channel

found in IHCs
has 10 transmem segments
believed to be a dimer with pore

nonselective cation channel, conducts K+ into IHC

79
Q

What NT do IHCs release?

A

Glutamate

80
Q

IHC at rest

A

Some (about 15%) channels open at rest

  • -> Constant leakage of Ca2+ into IHCs
  • -> Constitutive release of NTS

Spontaneous firing of the auditory nerve

Explains why relaxation causes hyperpolarization (the little bit of K that was getting in, making IHC less neg, is now blocked)

81
Q

IHCs can respond…

A

Bidirectionally

Different responses to bending

  1. Short->tall : stretch tip links -> open channels -> dep.
  2. Tall->short : relax tip links -> close channels -> hyp
    (kino-stereo push KINOS tall, stereos short)
  3. 90° push : don’t really cause bend, very little effect
82
Q

Hair bundle displacement v. R potential

A

Graded responses

Larger response w/more push

83
Q

How to encode for frequency?

A

Related to physical properties of basilar membrane

Flatten out –> base/oval: thick + rigid
apex/end: thin + flexible

~30 mm long in total

Stiff/oval window: respond to high frequencies

Flimsy/apex: respond to low freq

84
Q

Human hearing range

A

20 Hz - 20,000 Hz

85
Q

How is frequency encoded in hair cells?

A

Location on basilar membrane

  • Hair cells on different points on basilar mem have different compositions of ion channels

Each has different intrinsic oscillation freq - characteristic freq
If sound wave matches that particular hair cell’s freq, produces larger response

Sound waves at the characteristic frequency of a cell cause the largest fluctuation in membrane potential.

DUE TO DIFFERENT SETS OF CHANNELS

86
Q

How is intensity encoded in hair cells?

A

Louder sound = larger R potential = more NT release = faster firing of APs (in auditory nerve)

87
Q

What do the 3 rows of OHC in the organ of Corti do?

A

Not sensory neurons themselves, but do play important role

Through contractions/extensions, can alter stiffness of TECTORAL membrane

.˙. finetune

contract to sound stimulation + efferent innervation
respond to voltage Δs with contraction

88
Q

“Dancing” hair cell

A

Add electrode + whole-cell voltage clamp –> pass current into hair cell –> Δ in voltage –> hair cell contracts

89
Q

Causes of deafness

A

CSC

  1. Conductive deafness - has to do w/sound conductance itself
  2. Sensorineural deafness - problem with sound transduction pathway
    - issue in organ of Corti, hair cell degeneration
    - particularly at high freq., we only have 30,000 IHCs die with age (rock concert -> constant stretching -> break more easily)
  3. Or too much Ca2+ -> causes cell damage
90
Q

Which do we have more of - OHCs or IHCs?

A

Much more OHCs

~4x more

91
Q

Distribution of hair cells along BM

A

Pretty much uniform

92
Q

Resolving power

A

Resolving power much lower at high frequency

Ex: Can’t distinguish b/w 19,000 to 20,000 Hz, but can differentiate 200 to 210 Hz

93
Q

Chemosensation

A

Smell + taste

Primitive sense, exists even in single-celled organisms (ex: bacteria)

94
Q

Where does transduction take place for smell?

A

Olfactory epithelium

95
Q

Olfactory R neurons (ORNS

A

Bipolar sensory neurons containing olfactory Rs
Concentrated in cilia

Can fire APs

Die - must be constantly regenerated (same w/taste cells)

Apical side: numerous cilia embedded in mucus
Basolateral: project w/long axons to olfactory bulb

ORs are GCPRs

96
Q

ORN regeneration

A

Stem cells produce basal cells -> basal cells produce ORNs

Regenerate and express same # and types

97
Q

ORN number comparison

A

More ORNs = better smeller

Humans = 12 m
Rat = 15 m (olfactory bulb much larger comp.)
Dog = 1 b
98
Q

Cell types in olfactory epithelium and their functions

A

Olfactory receptor neurons (ORNs)

  • Bipolar sensory neurons containing olfactory Rs
  • Can fire APs

Basal cells

  • dividing stem cells
  • generate new ORNs

Supporting cells
- detoxify dangerous chemicals

Bowman’s gland
- secretes mucus

99
Q

Human odorant molecule detection threshold

A

0.1 nm –> we can detect at very low [ ]

100
Q

What is important for odorant detection?

A

Cilia

  • odorant molecules dissolved in saliva
  • bind to Rs in olfactory cilia
101
Q

Test: How do we know cilia of ORNs respond to odorants?

A
  1. Isolate ORNs
  2. Record currents elicited by various chemicals
    whole-cell voltage clamp
    inward current produces depolarization
    In cilia: we see large inward current
    In soma: we see little reaction

[Shows that ORN are concentrated in cilia]

102
Q

Olfactory R genes

A

Buck and Axel - First to clone OR genes

Found OR genes are GCPRs

These genes form large gene family, largest gene family in many species
3-5% of all genes

Mammalian olfactory R genes /= introns
No alternative splicing, all linked together
Gene is transcribed in full, in one piece in mammals

Many of them are pseudogenes
Expression is mono-allelic either express mother or father

103
Q

AC3

A

Adenyl cyclase 3
Cilia marker

Found only in apical epithelia, in cilia

A key enzyme mediating the cAMP signaling in neuronal cilia

Turns ATP -> cAMP

104
Q

Zoning v. non-zoning distribution

A

Lect. 18 [12/23]

105
Q

Olfactory transduction

A
  1. Odorant brings to R (GCPR)
  2. Golf (now GTP-bound) activates AC3
  3. AC3 [ATP -> cAMP]
  4. cAMP activates nonselective cation channel
    conduct Na+ and Ca in
    produces inward current
    —> depolarization —> R potential
    if large enough, R potential will produce AP
  5. Ca can flow through + activate Cl-gated channels
    Cl- will then flow out, helping to depolarize more

Depolarization = transduction of smell

106
Q

of human odorant Rs

A

~1,000 different odorant protein Rs

107
Q

Why attempts to express olfactory receptors in heterologous systems have failed?

A

In order to produce function, you need the pathway, not just the R alone. Need Gprotein (Golf), AC3, the channel…

Expressing R alone will not be enough

108
Q

What happens if you knock out components of olfactory transduction pathway?

A

Abolish olfactory signal transduction

109
Q

How are olfactory transduction responses turned off?

A

↓ [ ] of odorants, or move away from source

Binding will stop, process will end

110
Q

How does smell desensitization work?

A
  1. ↓ [cAMP] through hydrolysis by PDE
    then cation channel inactivated
  2. Ca can bind to calmodulin, which can bind to both channels (Na/Ca+, Cl-) to close them
  3. Over time, [Ca} ↓ through a Na/Ca exchanger, leading to reduced inward current, eventually ending process
111
Q

ORN responses

A

Some are specific, some are general

APs are concentration-dependent, more [ ] = faster firing
spontaneous alone

[19/23] Lect. 18

112
Q

Where do ORNs connect to?

A

ORNS send axons to the olfactory bulb

  • axons make connections with 2 types of cells in olf. bulb
    (1) mitral cells*
    (2) tufted cells

this occurs within the glomerulus, within the olf. bulb

*mitral cells - main projection neurons of the olf. bulb

Pair + project
- ORNs expressed in the same R (localized in same area) pair + project to glomerulus together

113
Q

Glomerulus

A

The glomerulus is located within the olfactory bulb of the brain where synapses form between the terminals of the olfactory nerve and the dendrites of mitral, periglomerular and tufted cells.

114
Q

What is the idea of “pair and project”?

A

Pair + project

- ORNs expressed in the same R (localized in same area) pair + project to glomerulus together

115
Q

Anosmia

A

Loss of sense of smell

  • can be caused by brain damage, virus, or age, or congenital

Due to abnormal development of olf system

116
Q

Odorant molecules vs. taste molecules

A

Odorants are often volatile airborne molecules

Tastants are often nonvolatile, soluble molecules

117
Q

NT in each type, and dep. v hyp.

A

x

118
Q

Human sensitivity to tastants

A

Quite weak - we need high [ ] to taste

The threshold concentration for tastantsis usually high

But for bitter substances, threshold is low

119
Q

5 taste modalities

A 
Sour
Salty
Bitter 
Sweet
Umami (glutamate)
120
Q

5 taste modalities associated w/essential body functions

A

Sour/salty - essential ions
Bitter - warning of toxicity
Sweet/umami - food intake

121
Q

Taste buds

A

Found in papilla

Different papilla have different buds

*add more

122
Q

Three cell types in taste buds

A
  1. Taste cells
  2. Supporting cells
  3. Basal cells (give rise to mature taste cells)
123
Q

Lifespan of taste cells

A

~1 month

124
Q

Taste cells

A

Taste receptor cells are

(1) polarized epithelial cells
have apical/bl sides, .˙. polarized

(2) short lived (~1 month)
(3) can be regenerated from basal cells
(4) have voltage-gated Na+, K+, and Ca2+ channels, release on bl side, and thus can fire action potentials

NT believed to be serotonin

125
Q

“Tongue map” argument

A

Five taste modalities are diffusely distributed on the tongue

There is no “tongue map”

126
Q

How do taste cells perceive different tastes?

A

3 encoding theories

(1) Labeled-line model
- everything predetermined
- each cell tuned to respond to certain taste
- each cell connected to certain gustatory nerve

(2) Cross-fibre model A
- taste cells can respond to all 5 tastes
- connected to certain gustatory nerve
- coding occurs in CNS

(3) Cross-fibre model B
- taste cells can respond to all 5 tastes
- connected to all gustatory nerves
- coding occurs in CNS

Labeled line = correct

127
Q

Taste transduction

A

Tastants depolarize via 2 mechanisms

(1) direct permeation
(2) indirect activation of GCPRs

NT believed to be serotonin

  • Trigger zone is not axon hillock (far away), it’s very close to nerve terminals, when terminals sufficiently depolarized, produce AP
128
Q

Taste transduction via ion channels

A

Salty channel conducts salt

Sour channel conducts protons
- channel formed by PKD1L3 and TrpP3

*more protons

129
Q

What is sour taste channel formed by?

A

PKD1L3 and TrpP3

130
Q

OTOP1

A

Proton channel important for sour taste

  1. Whole-cell recording from isolated taste cells
    Find that low pH can produce large current
    at neutral pH - normal current
    at low pH - large inward current
  2. Knock channels out, do whole-cell recording from isolated taste cells again
    Add low pH - no response
    .˙. we know these channels needed

Evidence good for OTOP1 being proton channel

131
Q

Taste transduction via GPCRs

A

Only 3 T1Rs. Why such a small number?

Knock-out of T1R2 attenuates sweet taste; umamitaste remains unaffected.

Knock-out of T1R1 abolishes umamitaste but leaves sweet taste intact.

Knock-out of T1R3 attenuates both sweet and umami taste

TRPM5 channels are temperature sensitive –is this related to temperature sensitivity of certain types of taste sensation?

132
Q

Taste Rs for 5 senses

A

Salty - ion channel

Sour - ion channel (PKD1L3 and TRPP3)

Bitter - GCPR (monomer T2R)

Sweet - GCPR (dimer T1R2 and T1R3)

Umami - GCPR (dimer T1R1 and T1R3)

133
Q

Types of taste receptor proteins

A

There are 4 in total

  1. T1R
    • T1R1, T1R2, T1R3
  2. T2R
134
Q

Taste transduction pathway for GCPRs

A

GCPR activated -> coupled to g-protein Gustducin -> Bind to PLCβ2 (breaks down lipids [PIP2] to produce two 2° msngrs, dieserglycerol and IP3

IP3 then binds to TRMP5 channel, which causes influx of Ca

135
Q

Main evidence for taste pathway components

A

Knock out experiments

136
Q

Knock out experiments for sweet/umami taste

A

Knock-out of T1R2 abolishes sweet taste; umami taste unaffected

Knock-out of T1R1 abolishes umami taste; sweet taste unaffected

Knock-out of T1R3 abolishes both sweet and umami taste

137
Q

TRPM5

A

Temp. sensitive cation channel., conducts Ca2+ influx

138
Q

What do cats not respond to?

A

Cats don’t have sweet Rs

T1R2 gene mutated (pseudogene)

139
Q

Sweet taste R

A

Sweet - GCPR (dimer T1R2 and T1R3)

140
Q

Umami taste R

A

Umami - GCPR (dimer T1R1 and T1R3)

141
Q

Bitter taste R

A

Bitter taste cells express ~30 T2Rs

Why so many?
- you want more Rs to detect more varieties of potentially harmful substances

We think T2Rs work as monomers

142
Q

Which tastes use GCPRs

A

Bitter, sweet, umami

Only difference is T R type

143
Q

Taste R localization

A

Different taste receptor proteins are expressed in different taste receptor cells

144
Q

Panda taste

A

umami not present

145
Q

Sea animals

A

Sweet and umami = pseudogenes

Bc they swallow their food whole

146
Q

Knock outs of various components

A

Slide 22/30 Lect. 19

Support labeled model line

147
Q

Support for labeled model line

A

Slide 22/30 Lect. 19

(1) Different taste receptor proteins are expressed in different taste receptor cells
(2) Knock out of a particular taste receptor protein results in the deficit of a specific taste modality
(3) Specific ablation of T1R2-, T2R-and PKD1L3-expressing cells results in the loss of a single taste quality (sweet, bitter and sour, respectively).(Genetically targeting diphtheria toxin to a defined subset of taste receptor cells)
(4) Knock out of PLCB2or TRPM5 eliminates sweet, bitter and umami taste, but not salty and sour taste.(5)Selectively expressing PLCB2 in T2R-expressing neurons in PLCB2 knock-out mice restores bitter taste, but not sweet and umami taste.
(6) Selectively expressing a taste-unrelated membrane receptor, which responds to a synthetic tasteless ligand, in sweet TRCs results in attraction of the engineered mice to the ligand. Conversely, expressing this receptor in bitter TRCs results in avoidance
(7) Expressing a novel bitter receptor in sweet cells results in attraction of the transgenic mice to a bitter compound (see figure in next slide), indicating that taste quality is determined by the TRC type, not by the taste receptor proteins or even the tastant molecules.

148
Q

TRPM5, PLCβ2 experiment in T2R cells

A

Rats drinking

Dissolve various tastes in H20
- w/higher [ ], they drink more/less

  1. Knock out TRPM5

==> TRPM5 is the taste transduction channel for sweet, umami and bitter taste

When knocked out, rats don’t show [ ] dependence to bitter/sweet/umami

  1. Knock out PLCβ2

==> PLCβ2 is an essential transduction molecule for sweet, umami and bitter taste

No [ ] dependence (to bitter/sweet/umami)

Put it back, response returns

Expressing PLCβ2 in T2R taste receptors cells restores bitter taste but not sweet or umami taste, supporting the notion that individual R cells are tuned to a single taste quality

149
Q

Engineering bitter R

A 
Developed novel (recombinant) bitter R
     responsive to particular molecule
  1. Feed molecule to wild-type animal
    • no [ ] difference/response, bc don’t have R
  2. Then express R on animal’s bitter cells, feed molecule
    • animals avoid compound
  3. Now express R on animal’s sweet cells, feed molecule
    • animals love it
      As long as you activate that R, you get the taste of the cell

Supports labeled-line model

150
Q

Miracle fruit

A

Makes sour -> sweet

Active ingredient : protein called miraculin (turns sour->sweet)

Miraculin itself does not taste sweet
- When taste buds are exposed to miraculin, the protein binds to the sweetness receptors

This causes normally-sour-tasting acidic foods, such as citrus, to be perceived as sweet

151
Q

How does miraculin change sour to sweet?

A

At low pH, miraculin Δs its confirmation to bind to sweet R

Binds to T1R2, where aspartame binds (art. sweetener)
=> causing sweet taste

Reduces effectiveness of sweeteners

At neutral pH, doesn’t do anything

=> Antagonist at neutral pH and functionally changes into an agonist at acidic pH

152
Q

Somatosensation

A

Touch, thermosensation, pain

153
Q

Somatosensory Rs

A

Touch, thermosensation, pain

Project to DRG nuerons

154
Q

Touch R types

A

Mediated by 4 Rs

Myelinated, large axons
==> fast conduction velocity

155
Q

Axon comparison

A

x

Which senses the fastest?

156
Q

Pain Rs

A

These Rs are basically free nerve endings (pretty much on skin surface)

Sharp pain = Aδ axons (myelinated, thinnish)

Slow/chronic pain = C axons (unmyelinated, thinnest)

157
Q

How do touch Rs respond to mechanical stimuli?

A

By expressing channels that are directly activated by membrane stretch

Ion channels are directly on PM

==> Transduction of mechanical force –> electrical signal
Mediated by mechanosensitive ion channels

Membrane stretch –> Channels directly opened –> Na influx –> Produce R potentials, depolarization –> AP firing (close to nerve ending)

(Nonselective cation channels), (ion channels mostly in nerve endings)

158
Q

Piezo channels

A

Piezo channel types respond to various membrane stretch

Inward current produced
- amp of current depends on mag. of pressure

Current profile:

  • respond to stronger mechanosensation
  • respond quickly (fast rise/decay)
159
Q

Piezo channel structure

A

Trimer w hole in middle

Channel can bend membrane

160
Q

How do we know Piezo channels are mechanosensitive

A

Purify protein -> place Piezo into lipid bilayer (no other components present) -> bend lipid bilayer (bending = mechanical force) -> record channel current

Piezo channels directly respond to mech. force

When Peizo2 knocked out of DRG neurons, no current

161
Q

Piezo mouse experiment

A
  1. Wild type - Piezo2 induces current
  2. Piezo2 KO in DRG neurons - no current
    (in some DRG neurons, Piezo needed)
    (touch sensitivity goes down, Piezo partly responsible for touch sensation)
  3. Piezo2 KO, overexpress Piezo1 (will it rescue current?)
    (Yes!)
  4. Express both Piezo1 + Piezo 2
    (Increased sensitivity to touch)

==> Overall, both important for touch, both mechanosensitive
Conduct inward current -> depolar. -> AP

162
Q

DRG axons for temp

A

Aδ axons (myelinated, thinnish)

C axons (unmyelinated, thinnest)

163
Q

2 temperature Rs

A

TrpV1
- capsaicin R, WARM/HOT temp

TrpM8
- cold temp

==> These channels express ion channels that are sensitive to different temps
=> Differential expression of Na+and K+channels modulates the temperature thresholds

Rs/channels located at the free nerve endings of DRG neurons)

164
Q

Minty gum perception

A

TrpM8 underlies cool feeling w/gum

165
Q

TrpV1 activated

A

Can bind to capsaicin to be activated

Can be activated by heat

Can be modulated by protons (larger response at lower pH)

166
Q

Spiciness

A

Not a “taste”

Mediated by pain Rs responsive to the face

Rs not found in taste buds or gustatory nerve endings

167
Q

Capsaicin molecular structure

A

Hydrophobic

Cold water somewhat helps, doesn’t remove it very effectively

MILK = best –> more fat, fat better dissolves hydrophobic substances

168
Q

Mice v. tree shrews

A

If you feed spicy mol (Cap2) to mice, with higher [ ] eat less

If you feed spicy mol (Cap2) to tree shrews, with higher [ ] eat more until reach high threshold (then slightly decline)

==> Then compare TrpV1 channels
transfect into kidney cells, record channels
Cap2 activates mice V1 Rs at low [ ]
Tree shrews need much higher [ ] before rejecting

Why?
- Single AA mutation in cap-binding pocket that decreases sensitivity

If you put tree shrew AAs in mouse, you dramatically ↓ sensitivity

169
Q

TrpV1 is activated by…

A

high temperature

Hardly no current under 35/35 C

Strongly activated by rising temps

170
Q

Camel and squirrel TrpV1 response profiles

A

Hot temp response

Camel and squirrel don’t respond to high temps, have high threshold/tolerance

Due to AA difference

171
Q

How do we know TrPV1 is an inherently heat-sensitive channel?

A

Purify protein -> place TrPV1 it in lipid bilayer (no other proteins present) -> Δ temp -> record channel current

At low temp, little/no response

At higher temps, increasingly large response

Channel protein itself activated by rising temp

(assumed to be due to AA sequence)

172
Q

TrpM8 activated by….

A

Activated by menthol and other cooling agents

Icilin = largest response, much more effective in activating M8 than menthol

No current at body temp
Current gets bigger+bigger with lower temps

173
Q

Pain-sensing DRG neuron groups

A

MTP

  1. Mechanical - high mech. force
  2. Thermal - above 35 C, below 5 C
  3. Polymodal - high mech. force, extreme temp (high freq.)
174
Q

All DRG?

A

x

175
Q

Channels most widely expressed in nociceptive neurons

A

TrpV1
TrpA1
ACIC

All nonselective cation channels

Produce R potential

176
Q

NaV 1.7

A

Na channel that seems to be vital for pain reception

Mutation of channel -> no pain of any type

These patients basically don’t express NaV 1.7 channels

w/o NaV 1.7, no APs

PKA phosphorylation can modulate response, but cannot alone open channel

177
Q

Ion channels involved in pain/pathway

A

TrpV1, TrpA1, ACIC
–> produce R potentials upon noxious stimuli

R potential travels down axon, reaches NaV 1.7
–> produces AP

NTs release to spinal cord

178
Q

What can modulate NaV 1.7 response

A

PKA phosphorylation can modulate response, but cannot alone open channel

Neurobiology (6 decks)

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