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Cell and Molecular Neuroscience > Mariq > Flashcards

Mariq Flashcards

1
Q

Anatomy of AchR

A

4 transmembrane regions / subunit
2 alpha
1 beta
1 gamma
1 delta

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2
Q

Acetylcholine History

A

Nerve stimulation vs Muscle
* Stimulate motor nerve – Muscles
did Notcontract
* Stimulate muscle - Contraction
* Is it a general anesthetic? Motor
disruption – Sensation intact!
* Limit curare to nerve – Muscle did
contract
* Expose muscle to curare – Muscle
did Notcontract
* Cannulate vasculature to NMJ –
Muscles did Notcontract

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3
Q

Evidence for chemical synaptic transmission, 1921 (Otto Loewi)

A
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4
Q

physostigmine

A

a reversible cholinesterase inhibitor.

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5
Q

Why Chemical Neurotransmission?

A

*Sign Inversion, integration and modulation
*Chemical NT allows for amplification!
*Muscle is big cell (150 μm diameter)
*Nerve terminal tiny (1.5 μm)
*NMJ: AP in nerve –> AP in muscle
*Ohm’s Law: V = IR
*How much current needed to depolarize muscle?
*How much current can be supplied by the neuron
if purely electrical communication?

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6
Q

Estimating Receptor Properties

A
  • Consider a channel that opens
    and closes
  • I = Nipo ; I = mean current, N = #
    of channels, i = current through
    single channel, po= probability
    of channel being open
  • Var = Ii(1- po); Var = variance
  • Plot Variance against Mean
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7
Q

Conductivity of AchR

A

28-32 pS

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8
Q

Ways to separate proteins

A

Size exclusion chromatography (mass)
ion exchange chromatography (charge)
affinity chromatography (binding)

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9
Q

which subunit of AchR controls gating?

A

delta

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10
Q

which subunit of AchR is required for binding to alpha-bungalotoxin?

A

alpha

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11
Q

which region of AchR controls conductance?

A

M2

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12
Q

Isolation and Identification of
Proteins

A
  • Need Tissues or Cells that Express Protein
  • Need Method to Separate Complex Mixture
    of Proteins by Physical Characteristics
  • Need Assay to Detect Protein (Purification)
    – Biochemical association
    – Physiological function
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13
Q

what ions does AChR conduct?

A

Na, K

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14
Q

What charateristic of AChR may change conductance?

A

(3) Ring(s) of charge around pore

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15
Q

Organization of AChR Channel Pore

A

*Chlorpromazine (CPZ) is channel
blocker
*UV flash causes reaction with protein
side chains
*Incubate AChR vesicles with [3H]-CPZ
and agonist. UV flash.
*Label found in every subunit
*All labeled amino acids in M2, at
relative positions 2’, 6’, 9’

Mutations in Pore Affect Blockers,
Desensitization, Conductance and Affinity
9’L: Part of Symmetrical Gate

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16
Q

a7/5HT3 Chimera: Ligand Binding

A
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17
Q

Ligand-gated Ion Channels

A
  1. Multimeric integral membrane glycoproteins
  2. Signal in two ways:
    * Change in membrane voltage - most
    common
    * Ca2+ entry - critical for synaptic plasticity
  3. Gating typically rapid (μsecs after ligand
    binding)
  4. Ion Selectivity:
    * Cationic, often non-selective (Na+, K+, Ca2+)
    * Cl- (GABA and Glycine receptors)
  5. Subject to modulation in a variety of ways
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18
Q

AChR alpha7 ligand

A

ACh

19
Q

AChR 5HT ligand

A

serotonin

20
Q

GABA receptors

A

I.g-amino-butyric acid (GABA) is the principle inhibitory
transmitter in the brain.
A. GABA receptors are cys-loop receptors; thus, they are
pentamers – at least four different types of subunits.
B. 6 asubunits, 3 bsubunits, 3 gsubunits, d, e, p, and rsubunits.
C. In general, a, b, and gsubunits are all required for receptor
function.
D. Only a limited number of subunit combinations exist.

21
Q

Glycine receptors

A

Glycine (Gly) is the predominant inhibitory transmitter in
the spinal cord.
A. Glycine receptors are pentamers of two different types of
subunits.
B. 4 asubunits, and 1 bsubunit
C. Stoichiometry is 3a:2b

22
Q

GABA Receptor Subunit Composition

A

Two GABA Binding Sites at
a-bInterfaces
Benzodiazepine Site at
a-gInterface

23
Q

How does diazapram effect GABA current

A

increases probability of channel opening

24
Q

how does barbituate effect GABA current

A

increases length of time channel is open

25
Q

Difference between cationic channels (ACh/Serotonin) and chloride channels (GABA/Glycine)?

A

cationic channels have acidic residues @ most intracellular spot, chloride channels have basic residues at that location

26
Q

Cys-loop receptors vs. Glutamate
Receptors

A
27
Q

criticisms of glutamate as NT

A
  • Too abundant–10 mM soluble constituent of brain
  • Involved in many biochemical/metabolic pathways
  • Broad action: depolarized essentially all neurons
  • No known mechanisms of activation or inactivation
28
Q

Classification of iGluRs

A

*NMDA - N-methyl-D-aspartate
– Competitive antagonist: AP5,
APV
– Pore blocker: MK-801
*AMPA
– Competitive antagonist: CNQX
*Kainate
– Competitive antagonist:
LY382884

29
Q

AMPA response is….

A

fast, short

30
Q

NMDA response is…

A

slow, long

31
Q

Structure of iGluRs

A

iGluRs are Tetramers
AMPARs are typically heteromers, but
can function as homomers
NMDARs are obligate heteromers, and
must include the GluN1 subunit

32
Q

iGluR Relevance to Neurological
Disorders

A

*Excitotoxicity/Stroke/Ischemia
*Epilepsy
*Neurodegenerative Disorders
*Psychiatric Disorders

33
Q

Receptor Cloning Strategies(Functional Expression)

A

`* Find tissue that expresses receptor
* Make total RNA
* Inject into Xenopus oocyte
* If receptor activity detected, make
cDNA library
* Make pools of cRNA
* Test in oocytes
* Fractionate pools, retest…
* Isolate single clone…
* Note: strategy dependent on
receptor that is single protein or
homo-oligomer

34
Q

What is the topology of iGlurs?

A
  • iGluRs ~ 1000 a.a.
  • No Cys-Cys loop
  • C-terminus phosphorylated
  • RNA editing
  • Alternative splicing: flip/flop region
    proximal to TM region
  • Loop 3 most conserved
  • Little sequence identity with AChRs,
    etc.
  • Regions of sequence identity with
    bacterial periplasmic glutamaine
    binding proteins
35
Q

________ Studies Reveal
Topology of iGluRs

A

Glycosylation

36
Q

GluR3’s ligand

A

AMPA

37
Q

GluR6’s ligand

A

Kainate

38
Q

Where does glutamate bind?

A

S1/S2 regions

39
Q

Topology of Ion Channels (AChR, iGluR, K)

A
40
Q

Gating and Stoichiometry of iGluRs

A
41
Q

Topology of glutamate receptors

A
42
Q

NMDARs’ general properties

A
  • voltage dependent
  • permeant to Ca2+
  • can function as coincidence detector
  • gated by Mg2+
  • Ligands
    – Need 2 molecules of glutamate & glycine
    – Glycine (or D-serine) is required co-agonist
  • Ionic permeability
    – Channel permeable to Na+, K+, and Ca2+
  • Voltage sensitivity/Mg2+block
    – At resting membrane potential, channel blocked by
    Mg2+ion.
    – As neuron becomes depolarized, Mg2+block is
    removed.
    – Region of “negative slope conductance”
    – “Coincidence detector”
  • Time course of NMDA currents
    – Slower and more prolonged than AMPA/Kainate
    receptor-mediated currents
43
Q

_____ is a Co-Agonist for NMDARs

A

Glycine

44
Q

Stargazin Protein

A

Founding Member of TARP
Family of Transmembrane
AMPA Receptor Regulatory
Proteins
3 roles:
* Obligate Chaperone
* Receptor Localization
* Receptor Function

Cell and Molecular Neuroscience (15 decks)

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