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PM4 - Neuroscience > Lieb > Flashcards

Lieb Flashcards

1
Q

energy consumption

A

20% of total energy

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2
Q

BBB

A

maintains neurogenesis, energy utilization, amyloid beta clearance, learning and memory

HEALTHY: tight junctions, controlled transcellular transport, p-Gp pump A-b -> HOMEOSTATIC MILIEU

AGED: leaky tight junctions, impaired energy utilization, cognition and neurogenesis, A-b accumulation -> NEUROTOXIC & NEUROINFLAMMATORY MILIEU

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3
Q

BBB
function

A

maintains neurogenesis, energy utilization, amyloid beta clearance, learning and memory

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4
Q

BBB
young & healthy

A

tight junctions, controlled transcellular transport, p-Gp pump A-b
-> HOMEOSTATIC MILIEU

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5
Q

BBB
aged

A

leaky tight unctions, impaired energy utilization, cognition and neurogenesis, A-b accumulation
-> NEUROTOXIC & NEUROINFLAMMATORY MILIEU

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6
Q

all cell types in NS (all metioned ones)

A

GLIA: astrocytes, myelinating glia (oligodendro, Schwann), ependymal, microglia

NEURONS

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7
Q

Glia cells

A
  • Astrocytes: influence neuronal growth, control extracellular milieu (glu, K+), similar receptors as in neurons
  • Myelinating glia: oligodendro & Schwann, myelin sheath for saltatoric transmission, oligodendrocytes for waste clearing and remodeling of neuronal connections
  • Ependymal cells: line ventricles, important during development
  • Microglia: waste clearing and remodelling of neuronal connections
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8
Q

Astrocytes

A

Glia cells
- influence neuronal growth
- control extracellular milieu (glu, K+)
- similar receptors as in neurons

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9
Q

Myelinating cells

A

Glia cells
- oligodendro & Schwann cells
- myelin sheath for saltatoric transmission
- oligodendrocytes for waste clearing and remodeling of neuronal connections

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10
Q

Oligodendrocytes

A

Myelinating glia cell
- waste clearing
- remodelling of neuronal connections

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11
Q

Ependymal cells

A

Glia cells
- line ventricles
- important during development

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12
Q

Microglia

A

Glia cells
- waste clearing
- remodelling of neuronal connections

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13
Q

cell types important for cranial waste clearing

A
  • oligodendrocytes
  • microglia
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14
Q

cell types important for remodelling of neuronal connections

A
  • oligodendrocytes
  • microglia
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15
Q

NEURONS
parts

A
  • somata (organelles)
  • membrane (isolator)
  • cytoskeleton (microtubuls, microfilaments, neurofilaments)
  • axon (output)
  • dendrites (input)
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16
Q

NEURONS
Types + Example

A
  • unipolar (invertebrate neuron)
  • bipolar (bipolar neuron retina)
  • pseudo-unipolar (DRG neuron)
  • multipolar (motor neuron, pyramidial cell, purkinje-cell)
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17
Q

invertebrate neuron
neuron type

A

unipolar

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18
Q

DRG neuron
neuron type

A

pseudo-unipolar

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19
Q

motor neuron
neuron type

A

multipolar

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20
Q

purkinje cell
neuron type

A

multipolar
cerebellar neuron

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21
Q

pyramidial cell
neuron type

A

multipolar
hippocampal neuron

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22
Q

NEURONS
Soma

A

high K+, low Na+
location of organells
- nucleus
- rER for membrane proteins
- free ribosomes for cytosolic proteins
- sER for protein folding, regulates internal Ca2+, post-translationl modifications
- mitochondria

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23
Q

NEURONS
cytoskeleton

A

MICROTUBULES
- anterograde kinesin, retrograde dynein
- assembly via GTP-hydrolysis
- drug target (vinca alkaloids assembly, taxene disassembly)

MICROFILAMENTS: 2 actin strands -> fiber -> mesh
NEURONFILAMENTS: structural integrity of esp. large axons

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24
Q

microtubules

A
  • anterograde kinesin, retrograde dynein
  • assembly via GTP-hydrolysis
  • drug target (vinca alkaloids assembly, taxene disassembly)
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25
Q

microfilaments

A

2 actin strands -> fiber -> mesh

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26
Q

neurofilaments

A

structural integrity of esp. large axons

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27
Q

NEURON
axon

A

area of output
- axon hillock (initiation segment, no rER)
- axon proper (wire, myelin sheaths, can form axon collaterals)
- axon terminal (synapse, chemical or electrical)

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28
Q

locus of AP generation

A

Axon hillock = initiation segment

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29
Q

axon hillock

A

= initiation segment
locus of AP generation

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30
Q

axon proper

A

electrical wire
myelin sheaths
can branch into axon collaterals

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31
Q

axon terminal

A

= synapse, terminal button
chemical or electrical

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32
Q

NEURONS
dendrites

A

area of input
polyribosomes

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33
Q

polyribosomes

A

hallmark of dendrites

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34
Q

Nernst equation

A

calculates equilibrium potential across the membrane of one specific ion

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35
Q

equilibrium potentials (37°C)

A

calculated by Nernst equation
K: -80mV
Na: +62mV
Ca: +123mV
Cl: -65mV

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36
Q

ion concentrations (EC and IC)

A

K: 5nM EC, 100nM IC
Na: 150 EC, 15nM IC
Ca: 2nM EC, 0.0002nM IC
Cl: 150nM EC, 13nM IC

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37
Q

5nM EC, 100nM IC

A

K

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38
Q

150nM EC, 15nM IC

A

Na

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39
Q

2nM EC, 0.0002nM IC

A

Ca

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40
Q

150nM EC, 13nM IC

A

Cl

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41
Q

-80 mV equilibrium potential

A

K

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42
Q

+62 mV equilibrium potential

A

Na

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43
Q

+123 mV equilibrium potential

A

Ca

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44
Q

-65 mV equilibrium potential

A

Cl

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45
Q

equilibrium potential K

A

-80 mV

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46
Q

equilibrium potential Na

A

+62 mV

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47
Q

equilibrium potential Ca

A

+123 mV

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48
Q

equilibrium potential Cl

A

-65 mV

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49
Q

ion concentration (EC and IC) K

A

5nM EC, 100nM IC

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50
Q

ion concentration (EC and IC) Na

A

150nM EC, 15nM IC

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51
Q

ion concentration (EC and IC) Ca

A

2nM EC, 0.0002nM IC

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52
Q

ion concentration (EC and IC) Cl

A

150nM EC, 13nM IC

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53
Q

Goldman-Hodgkin-Katz equation

A

calculates the conductance of a neuron (membrane potential) at a specific time point (specific ion concentration)
in “normal” conditions usually -65 mV

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54
Q

calculates the conductance of a neuron (membrane potential) at a specific time point (specific ion concentration)

A

Goldman-Hodgkin-Katz equation

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55
Q

calculates equilibrium potential across the membrane of one specific ion

A

Nernst equation

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56
Q

measurment of ion flow

A

patch-clamp method
- cell attached
- whole cell
- outside-out
- inside-out

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57
Q

effect of outward stimulation

A

stimulus -> receptor potential (dependent on voltage of stimulus) -> AP (if threshhold potential is reached, frequency dependend on receptor potential)

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58
Q

parameters determing ion flow

A

electric driving gradient (ohms law)
ionic driving gradient

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59
Q

Na+/K+ ATPase

A

tetramer (2a2b)

OPENING:
- inward open when ATP bound
- 3 Na bind
- ATP hydrolysis -> closed
- ADP release -> open (outward)
- Na dissociates, 2 K bind
- inward open throuigh ATP binding

pathophysiology dependend on SU used, a1 omnipresent, a2 in muscle and brain, a3 in brain

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60
Q

Na+/K+ ATPase
opening process

A

tetramer (2a2b)

  • inward open when ATP bound
  • 3 Na bind
  • ATP hydrolysis -> closed
  • ADP release -> open (outward)
  • Na dissociates, 2 K bind
  • inward open throuigh ATP binding
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61
Q

Na+/K+ ATPase
structure

A

tetramer (2a2b)

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62
Q

diseases caused by Na+/K+ ATPase defect (examples)

A

FHM, RDP, AHC, CAPOS

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63
Q

FHM

A

familial hemiplegic migraine
can be caused by Na+/K+ ATPase defect

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64
Q

RDP

A

rapid-onset dystonia parkinsonism
can be caused by Na+/K+ ATPase defect

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65
Q

AHC

A

alternating hemiplegia of childhood
can be caused by Na+/K+ ATPase defect

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66
Q

CAPOS

A

Cerebellar ataxia
Areflexia
Pes cavus
Optic atrophy
Sensorineural hearing loss
can be caused by Na+/K+ ATPase defect

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67
Q

Ca2+ ATPase

A

3 main groups: SERCA, PMCA, SPCA

OPENING:
- 2 Ca bind inside
- Mg-ATP binding causes slight conformational change
- ATP-hydrolysis causes further change
- Ca dissociates inside, exchanged by 2 H+
- conformation with H+ unstable
- reverse to original state and Mg & H+ release

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68
Q

Ca2+ ATPase
opening process

A
  • 2 Ca bind inside
  • Mg-ATP binding causes slight conformational change
  • ATP-hydrolysis causes further change
  • Ca dissociates inside, exchanged by 2 H+
  • conformation with H+ unstable
  • reverse to original state and Mg & H+ release
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69
Q

Cl tranpsort

A

dependend on K gradient established by Na/K ATPase
KCC2 -> cotransport (efflux)
neonatal NKCC1 causes K efflux and Cl influx

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70
Q

NKCC1

A

neonatal Cl transporter
K efflux, Cl influx
re-expression in adults can cause epilepsy

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71
Q

KCC2

A

K-Cl cotransporter
K and Cl efflux
dependend on Na/K ATPase generated K gradient

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72
Q

receptor potential
definition

A

(small) fluctuations caused by ion flow (usually positive)

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73
Q

EPSP

A

ecitatory post-synaptic potential, addition of many (excitatory) receptor potentials

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74
Q

AP

A

action potential
generated if cell depolarizes above a certain threshhold, usually by temporal or spatial suzmmation of EPSPs
sometimes one EPSP is sufficient

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75
Q

IPSP

A

inhibitiory post-synaptic potential
inhibiting signal of e.g. interneurons

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76
Q

AP architecture and corresponding ion

A

rising phase -> Na
decay slope -> K
overshoot -> K

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77
Q

Voltage gated ion channels

A

essential for AP generation, defects cause so called channelopathies
usually rapid activation, fast inactivation via pore collapse and repeated ctivation leads to slow/inactivated state

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78
Q

VGSC
structure

A

voltage gated sodium channels

  • kinda monomer (one alpha, one auxiliary beta)
  • 4 TM domains with 6 TM regions each (24TM)
  • VOLTAGE SENSOR S1-4 with S4 positively charged
  • PORE FORMATION by S5-6
  • MODULATION by linker between dom 1&2
  • INACTIVATION by linker between dom 3&4
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79
Q

VGSC
opening

A

voltage gated sodium channels

  • IC positive charge pushes S4 outwards
  • pore opens
  • linker between domain 3&4 collapses into the pore
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80
Q

VGSC
drug target

A

local anaesthetic (LIDOCAINE)
epilepsy
chronic pain
cardiac arrhythmia

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81
Q

Pain sensation and voltage-gated channels

A

VGSC play an important role in pain sensation (esp. NaV1.7-1.9)
one type (1.7) can cause in- and decreased pain

  • PRIMARY ERYTHROMELALGIA: mutation in SCN9A cause e.g. lowering of threshhold potential
  • PEPD: paroxysmal extreme pain, e.g. gof in SCN9A leads to no pore collapse
  • CIPA: complete insensitivity to pain, e.g. no opening
82
Q

primary erythromelalgia

A

usually painless stimuli (e.g. touch) are percieved as painful
cause e.g. mutation in SCN9A (NaV1.7) that cause lowering of threshhold for receptor-opening

83
Q

PEPD

A

paroxysmal extreme pain disorder
caused by e.g. gof mutation in SCN9A that alters biophysical properties
e.g. no pore collapse

84
Q

CIPA

A

complete insensitivity to pain
caused by e.g. SCN9A mutation that leads to no opening of NaV1.7

85
Q

KV channels
types

A

4 subfamilies depending on ligand and structure (TM domains)

  • Kir: K inward rectifying channels, 2TM
  • K2P: 2 pore K channel, 4TM
  • KCa: Ca gated K channel, 6-7TM
  • KV: voltage gated K channel, esp. KV11.1 important
86
Q

KV channels
structure

A

TETRAMER of 4 alpha-SU with 6TM regions each

  • VOLTAGE SENSOR S1-4 with S4 positively charged
  • PORE FORMATION by S5-6
  • MODULATION by linker between dom 1&2
  • INACTIVATION by linker between dom 3&4
87
Q

KV channels
opening

A

like NaV channels

  • IC positive charge pushes S4 outwards
  • pore opens
  • linker between domain 3&4 collapses into the pore
88
Q

KV11.1

A

target of class II antiarrhythmics
mutations can lead to LQTS
mutations (SNPs) can be localized in RXR (ER retention motif) or influence glycosilation

every drug is screened against KV11.1 interaction –> could cause arrhythmia

89
Q

CaV channels

A

three classes depending on their threshhold
activity is modified by kinases, GPCRs, etc

90
Q

CaV channels
selectivity filter

A

towards K the size and Cl the charge
Na very similar -> 2 neg charges transmit ion to two other neg charges -> Na only one +

91
Q

CaV channels
structure

A
  • alpha1 SU as channel with 24 TM helices in 4 regions
  • beta SU auxilliary
  • alpha2delta SU for proper localization
92
Q

CaV channels
drug target

A
  • DHP: dihydropyridine, binds allosteric inactivated channel (modulator)
  • VERAPAMIL: binds in pore and prevents ion flow (channel blocker)
93
Q

DHP

A

dihydropyridine
binds allosteric to inactivated CaV

94
Q

Verapamil

A

channel blocker for CaV
binds in pore

95
Q

super agonist

A

more activation than original compoundu

96
Q

full agonist

A

activation like original compound

97
Q

partial agonist

A

activation less than original compound by e.g. only causing partial opening to a intermediate state

98
Q

antagonist

A

no activation, but any basal activity is usually not prevented

99
Q

inverse agonist

A

also inhibition of basal activity (less activity than when there is no ligand present)

100
Q

allosteric modulators

A

change in activity by binding away from original binding site
can influence affinity or effficacy

101
Q

competitive inhibition

A

drug competes with original compound since both bind the same binding site

102
Q

reversible inhibition/activation

A

drug has same affinity as original compound and can therefore be displaced over time

103
Q

irreversible inibition/activation

A

drug has increased affinity and cannot be displaced, new receptor/protein etc hs to be produced in order to regenerate

104
Q

types of signal transmission

A

axodendritic
axosomatic
axoaxonic

105
Q

EPSP generating sites

A

active zones, some synapses have one active zone, some have multiple

106
Q

active zone

A

EPSP generating site, some synapses have one, some have more

107
Q

electrical synapse

A

ion flow from one cell to the next via gap junctions
one gap junction are two connexons (6 connexins each) tethered by ionic interaction
negative charges witthin the gap junction prevent Cl- flow

108
Q

types of NT

A

AA
amines
neuropeptides

109
Q

NT
AA

A

glutamate
GABA
glycine

110
Q

NT
amine

A

dopamine
serotonin
histamine
(nor-) epinephrine
Acetylcholine

111
Q

NT
Neuropeptides

A

CCK
SP
NPY
TRH
VIP
SST
dynorphins, enkephalins

112
Q

vesicular NT transporters

A
  • VMATs: monoamines, 2H+
  • VAChT: ACh, 2H+
  • VGAT: GABA and glycine, nH+
  • VGLUTs: glutamate, nH+

work because of H+ gradient (proton pump ATPase)
drug target as alternative to NT reuptake, not yet clinically used

113
Q

VMATs

A

vesicular monoamine NT transporter
transport in exchange for 2H+

114
Q

VAChT

A

vesicular ACh transporter
in exchange for 2H+

115
Q

VGAT

A

vesicular GABA or glycine transporter
exchnage for nH+

116
Q

VGLUTs

A

vesicular glutamate transporter
in exchange for nH+

117
Q

vesicular NT transporters
drug target

A

alternative to targeting NT reuptake (e.g. SNRIs) but not yet clinically applied

118
Q

NT-vesicle fusion

A

PRIMING: syntaxin 1A and SNAP-25 (tSNAREs) bind to Synaptobrevin (vSNARE) with Munc18 as intermediate

Ca2+ required for full zppering and membrane fusion
Ca2+ via CaV in close proximity (RIM, Munc , Rab and tSNAREs bound to CaV)

kiss & run or full fusion

119
Q

NT-vesicle fusion
types and recycling

A

kiss and run or full fusion
recycling: ultra-fast endocytosis at kiss-an-run, otherwise clathrin mediated or bulk endocytosis

120
Q

NT vesicle fusion
drug target

A

trageted by several toxins
Botolinum toxin (inhibition)
Tetanus toxin (GABA vesicles -> excitation)

121
Q

NT release
drug targets (excitatory)

A
  • NaV channels
  • CaV channels (e.g. alpha2delta SU)
  • vesicle surface proteins
  • postsynaptic receptors
122
Q

NT release
drug targets (inhibitory)

A
  • GABA transaminase
  • GAT1
  • post-synaptic Cl channels
123
Q

receptors monoamine neuron

A

VMAT
DAT/NET/SERT for reuptake

124
Q

receptors acteylcholine neuron

A

VAChT
AChEsterase cleaves i synaptic cleft
ChT for choline reuptake

125
Q

receptors GABA neuron

A

three-part synapse
VGAT
GAT1 for direct reuptake
GAT3 for glial reuptake
GABA transaminase for GABA to Glu
Glutamine synthase for Glu to Gln
SN1/SN2 for glial Gln export
SAT3 for Gln uptake in neuron

126
Q

receptors glutamate neuron

A

three-part synapse
VGLUTs
GLT for direct reuptake
GLT/GLAST for glial reuptake
Glutamine synthase for Glu to Gln
SN1/SN2 for glial Gln export
SAT3 in neuron for Gln uptake

127
Q

DAT

A

dopamine reuptake transporter

128
Q

NET

A

norepinephrine reuptake transporter

129
Q

SERT

A

serotonin reuptke transporter

130
Q

ChT

A

choline transporter for choline reuptake

131
Q

AChE

A

ACh esterase for cleavage ito acetat and choline

132
Q

GAT1

A

GABA transporter for neuronal GABA reuptake

133
Q

GAT3

A

GABA transporter for glial GABA reuptake

134
Q

GABA transaminase

A

converts GABA to Glu
in glial cells important for GABA recovery

135
Q

Glutamine synthase

A

converts Glu to Gln
in glial cells important for GABA and Glu recovery

136
Q

SN1

A

transporter in glia cells for Gln export

137
Q

SN2

A

transporter in glia cells for Gln export

138
Q

SAT3

A

in neurons for Gln uptake

139
Q

GLT

A

in neurons for direkt Glu reuptake
in glia cells (or GLAST) for glial reuptake

140
Q

GLAST

A

in glia cells (or GLT) for Glu reuptake

141
Q

NT reuptake

A

dependend on NA/K gradient (Na/K ATPase)
facilitated by NSS (neurotransmitter sodium symptorter)
LeuT for biogenic amines, GABA and glycine
EAAT for excitatory AA (Glu)

142
Q

opening process EAAT

A

excitatory AA transport
outward open -> Glu and Na bind
outward occluded, inward occluded
inward open -> Glu and Na dissociate, K binds
reverse process -> K dissociates

143
Q

three part synapse

A

pre-a dn post-synaptic neurons and glia cell
important in glutamatergic and GABAergic neurons for reuptake

144
Q

NT reuptake transporter
drug target

A

ANTIDEPRESSANTS: SSRI, SNRIs
TIAGABINE: anticonvulsants, reduced GAT1 (prolonged GABA signalling)
PSYCHOSTIMULANTS: amphetamine, cocaine block DA transporter

145
Q

amphetamine

A

blocks DAT -> reduced DA reuptake

146
Q

cocaine

A

blocks DAT -> reduced DA reuptake

147
Q

SSRIs, SNRIs

A

antidepressants
reduced serotonin reuptake (or norepinephrine) (SERT, NET)

148
Q

Tiagabine

A

anticonvulsants
inhibit GAT1 -> reduced GABA reuptake

149
Q

ionotrophic glutamate receptors
examples

A

AMPA
NMDA
kianate

150
Q

ionotrophic glutamate recepors
structure

A

4SU form tetrameer
EC amino-terminal domain
EC ligand-binding domain
TM-domain: 3 alpha-helices (M1, M3-4) and loop (M2) as selectivity filter

151
Q

AMPA receptor

A

ionotrophic glutamate recepor
conducts positive ions
Ca2+ conductance of GluA2 SU prevented by RNA-EDITING (Q to R –> argine is pos. charged)

152
Q

NMDA receptor

A

ion flow blocked by Mg2+ binding in pore
IC pos. charge (Na from AMPA R) “kicks” Mg out
ion flow including Ca
Ca leads to signalling and more AMPA receptors (LTP)

153
Q

long term potentiation

A

AMPA easier activated
if enough activated than Ca flow through NMDA receptors
Ca leads to more AMPA receptors
if once a signal was strong enough, the nxt time the signal does not be as strong

154
Q

membrane localization of AMPA

A

interaction with several proteins
e.g. TARPgamma2 in ER, or PSD-95 on membrane (tethers to other proteins)

155
Q

ionotrophic glutamate recepors
drug target

A

anti-epileptic drugs

  • PMP (perampanel): stabalizes closed AMPA 8reduced ion flow)
  • VALPORATE: targets NMDA
  • FELBAMATE: targets NMDA
156
Q

PMP

A

perampanel
anti-epileptic
stabalizes closed AMPA (reduced ion flow

157
Q

Perampanel

A

PMP
anti-epileptic
stabalizes closed AMPA (reduced ion flow

158
Q

Valporate

A

anti-epileptic
targets NMDA

159
Q

Felbamate

A

anti-epileptic
targets NMDA

160
Q

drug targeting AMPA

A

PMP (perampanel)

161
Q

drug tageting NMDA

A

Valporate
Felbamate

162
Q

TARPgamma2

A

protein binds to AMPA in ER
required for proper localization

163
Q

PSD-95

A

protein, binds to AMPA in membrane
tethers it to other proteins in (synaptic) membrane

164
Q

cys-loop receptors
examples

A

inhibitory: GlyR, GABA-A
excitatory: nAChR, 5HT3R

165
Q

cys loop receptors
structure

A

PENTAMER, each SU has
EC amino-term domain
EC ligand-binding dom
TM dom: 4 alpha helices, M2 of all 5 forms pore

166
Q

M2 of Cys-loop receptors vs ionotrophic glutamate receptors

A

glutamate rec: tetramer, M2 forms selectivity filter
cys-loop: pentamer, M2 forms pore

167
Q

GlyR
ion, disease

A

cys-loop receptor (PENTAMER)

  • Cl conducting
  • disease relevant in fainting goat, startle disease, epilepsy
168
Q

GlyR
conformations

A

cys-loop receptor

  • open: all residues allow pore with r > 2A
  • closed: L9 of M2 in pore
  • inactivated: P2 of M2 in pore
169
Q

GlyR
drug target

A

PTX (picrotoxin)
blocks GlyR -> hyperactivation due to desinhibition

170
Q

GlyR
physiological circuit example

A

spinal cord reflex circuit: pain from stubbed toe lead to inhibition of flexor muscles and activation of extensor, opposite reaction on other leg for stabilization

171
Q

GABA-A
structure

A

cys-loop receptor
2 alpha, 2 beta, 1 gamma (PENTAMER)
GABA binding site between alpha and beta SU (2 binding sites)

172
Q

GABA-A
localization

A

synaptic: fast and short signal
extra-synaptic: longer but less strong signal

173
Q

GABA-A
drug target

A

target for most anti-epileptic drugs (BENZODIAZEPINES)

  • DIAZEPAM: allosteric moulator, increased activation probability
  • PTX: picrotoxin, blocks pore and hyperactivation due to desinhibition
  • ALP: alprazolam, allosteric modulator increases Cl flux
  • PROPOFOL: general anaesthetic, fast acting
174
Q

Picrotoxin

A

PTX
blocks pore of GABA-A and GlyR
leads to hyperactivation due to desinhibition

175
Q

PTX

A

picrotoxin
blocks pore of GABA-A and GlyR
leads to hyperactivation due to desinhibition

176
Q

Diazepam

A

Benzodiazepam
acts on GABA-A
allosteric moulator, increased activation probability

177
Q

ALP

A

alprazolam
Benzodiazepine
acts on GABA-A
allosteric modulator increases Cl flux

178
Q

Aprazolam

A

ALP
Benzodiazepine
acts on GABA-A
allosteric modulator increases Cl flux

179
Q

Propofol

A

acts on GABA-A
general anaesthetic, fast acting

180
Q

nAChR

A

excitatory cys-loop receptor (PENTAMER)
Na influx upon 2 ACh binding
primarily in muscle end plate

181
Q

nAChR
drug target

A

depolarising: directly in nAChR, cause massive Na influx which prevents further activation after initial activation, e.g. succinylcholine

non-depolarising: can act on ACh rather than receptor, but CURARE is non-activating competitor to ACh and binds nAChR (muscle relaxans)

182
Q

curare

A

poison that competitively binds nAChR in a non-activating fashion
used as muscle-relaxans in history

183
Q

GPCRs
classes

A

Class A: rhodopsin receptor family (e.g. DA-receptors)
Class B: secretin receptor family (e.g GABA-B)
Class C: mGlu-like receptor family, can signal as monomers

184
Q

G proteins
types

A

Gs: activate AC, more cAMP, more PKA
Gi: inhibit AC
Gq: activate PLC, IP3 and DAG from PIP2

185
Q

G proteins
targets

A

AC: adenylyl cyclase, activating or inhibiting (Gs or Gi), more cAMP leads to more active PKA

PLC: IP3 and DAG from PIP2, IP3 increases IC Ca, DAG activates PKC and other

Ion channels: opens K (hyperpolarization), inhibits Ca (red. NT release)

PLA2: opens K and inhibits Ca channels

186
Q

AC

A

adenylyl cyclase
target of Gs and Gi
more cAMP leads to more active PKA

187
Q

PLC

A

phospholipase C
target of Gq
IP3 and DAG from PIP2 -> IP3 increases IC Ca, DAG activates PKC and other

188
Q

ion channels and G proteins

A

can interact with each other
opens K (hyperpolarization)
inhibits Ca (red. NT release)

189
Q

PLA2

A

phospholipase A2
target of G proteins, influences ion channels
opens K (hyperpolarization) and inhibits Ca (red. NT release)

190
Q

desensitization of GPCRs

A

GRK phosphorylates GPCRs
- phosphorylation as internalisation signal and eventual lysosomal degradation
- process reversed by phosphotases

beta-arrestin can bind phosphorylated GPCR
- promotes endocytosis
- blocks GPCR signalling

191
Q

GRK

A

G protein-coupled receptor kinase
phosphorylates GPCRs
- phosphorylation as internalisation signal and eventual lysosomal degradation
- process reversed by phosphotases
- phosphorylation facilitates beta-arrestin binding

192
Q

beta-arrestin

A

modulation of GPCR activity
- binds phosphorylated GPCR (GRK)
- promotes endocytosis
- blocks GPCR signalling

193
Q

dopamine receptors

A

GPCRs Class A

  • D1-like: DRD1 and DRD5, Gs coupled
  • D2-like: DRD2-4, Gi coupled

D2Sh: short, pre-synaptic involved in DA synthesis, storage and release
D2Lh: classic post-synaptic receptor

194
Q

dopamine receptor
drug target

A

PRAMIPREXOLE: treatment of AD als alternitive to L-DOPA (to delay DOPA-induced dyskinesia), agonist for D3R

195
Q

Pramiprexole

A

D3R agonist (DA receptor)
reatment of AD als alternitive to L-DOPA (to delay DOPA-induced dyskinesia)

196
Q

drug as alternative to L-DOPA (AD)

A

pramiprexole
D3R agonist (DA receptor)
used to delay DOPA-induced dyskinesia

197
Q

GABA-B

A

GPCR Class B

  • functions as HETERODIMER with GB1 (ligand bindng) and GB2 (function)
  • ligand binding leads to conformational shift (twisting and shift of TM domains) -> now G protein can interact
  • Gi coupled, beta-gamma activate GIRK (K influx)
  • target of Baclofen
198
Q

GABA-B
drug target

A

BACLOFEN: muscle spasticity, allosteric modulator
off-label use for alcohol addicts (manages cravings)

199
Q

Baclofen

A

GABA-B allosteric modulator
indicated for muscle spasticity
off-label use for alcohol addicts

200
Q
A

PM4 - Neuroscience (3 decks)

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