Neurotransmiters & their Receptors Flashcards Preview

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Flashcards in Neurotransmiters & their Receptors Deck (49):
1

Types of receptors

Ionotropic and metabotropic

2

Ligan-gated ion channels

ionotropic
1. neurotransmitter binds
2. channel opens
3. ions flow across membrane

3

g-protein coupled receptors

metabotropic
1. neurotransmitter binds
2. g-protein is activated
3. (g-protein subunits or intracellular messengers/effector protein) modulate ion channels
4. ion channel opens
5. ions flow across membrane

4

ionotropic channels

ionotropic receptors
fast receptor
intra-molecularly coupled; single protein; binding site and ion channel in single molecule
either depolarization(ESPS, IPSP) or hyperpolarization(IPSP)

5

metabotropic channels

slow
inter-molecularly coupled
activates intracellular messengers that open/close ion channels/ionotropic receptor
* key function: homeostasis and development (gene transcription)

6

Glutamate

ionotropic: AMPA, NMDA, Kainate
metabotropic: Glutamate

7

GABA

ionotropic: GABA
metabotropic: GABA_B

8

ACh

ionotropic: nACh
metabotropic: mACh; muscarinic

9

Serotonin & Purines

also have ionotropic and metabotropic receptors

10

General architecture of ligand gated receptors ; ionotropic receptors

1. AMPA
2. NMDA
3. Kainate
4. GABA
5. Glycine
6. nACh
7. Serotonin
8. Purines

1. AMPA - quadromer
2. NMDA - pentomer
3. Kainate - pentomer
4. GABA - hexomer
5. Glycine - pentomer
6. nACh - quadromer
7. Serotonin - monomer
8. Purines - 7

11

nAChR

nicotinic Acetyl Choline Receptor
Pentamericprotein
- neuromuscular juction: 2 alpha, beta, gamma, delta
- neuronal ACh: 3 alpha, 2 beta

non-selective cation channels

12

EPC - end plate current

End plate: neuromuscular junction
EPC occurs in both directions based on clamped voltage
1. -100mV (~E_K): Na+ inward current - to depolarize
2. resting membrane potential: Na+ and K+ - to depolarize
3. 0mV: equal net flow
4. +70mV(~E_Na): K+ outward current - to hyperpolarize

* ions do not move if voltage clamped is close to its equilibrium potential

13

General architecture of g-protein coupled receptors; metabotropic receptors

Glutamate
GABA_B
Dopamine
NE, Epi
Histamine
Serotonin
Purines
Muscarinic

Glutamate : ...
GABA_B : dimeric
Dopamine : pentomeric
NE, Epi : pentomeric
Histamine : pentomeric
Serotonin : 7
Purines : ...
Muscarinic : pentomeric

14

GPCR - G-protein coupled receptor

Largest in receptors
5% pf genes in C.elegans
1000 involved in sense of smell

signaling molecules : protein, peptide, amino acid derivatives, fatty acids
* all have the same general structure: span membrane 7 times (serpentine receptor)

N-terminus: extracellular
C-terminus: intracellular - G-protein bound

alter activity of effector proteins/trimeric G-proteins

G-protein bind guanine nucleotides

15

Trimetric G-protein

alpha, beta, gamma subunits
alpha, gamma linked to the membrane covalently
beta and gamma attached and referred as G_bettagamma

Resting state: G_alpha + GDP + G_bettagamma

Receptor activated: binds to G_alpha, GDP released, GTP binds, G_alpha released to bind to active effector, GTP hydrolysis to GDP, back to resting state

16

Time course of G-protein activation

FRET: Fluorescent Resonance Energy Transfer
G_alpha: CFP
G_betta: YFP

CFP light excites YFP when close

cAMP which activates GPCR realse G_alpha from G_bettagamma; reduce in YFP observed

17

Chimeric protein; adenylyl cyclase

to determine which domains of the receptors interact with G-proteins
C3 loop

18

Cardiac ACh receptors

Muscarinic ACh receptor; inhibition
G_alpha_i --> G_alpha is not a regulator
G_bettagamma --> released to activate K+ channel: hyperpolarize; inhibit; make muscles more difficult to contract

19

Small molecule neurotransmitter

Acetylcholine

Amino acid - glutamate, aspartate, GABA, glycine
Purine - ATP
Biogenic amine - catecholamine (dopamine, norepinephrine, epinephrine), indoleamine (serotonin), imidazoleamine (histamine)

20

Peptide neurotransmitter

large density neurotransmitter

21

ACh

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

Acetyl Choline
Excitatory
Choline+acetyl CoA
CAT
AchEase
small clear

22

Glutamate

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

Excitatory
gllutamine
glutaminase
transporters
small clear

23

GABA

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

inhibitory
glutamate
GAD
transporters
small clear

24

Glycine

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

Inhibitory
serine
phosphoserine
transporters
small clear

25

Catecholamine

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

(epinephrine, norepinephrine, dopamine)

excitatory
tyrosine
tyrosine hydroxylase
transporters, MAO, COMT
small dense-core, large irregular dense core

26

serotonin

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

excitatory
tryptophan
tryptophan hydroxylase
transporters, MAO
large, dense-core

27

histamine

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

excitatory
histidine
histidine decarboxylase
transporters
large, dense-core

28

ATP

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

excitatory
ADP
mitochondrial oxidative phosphorylation; glycolysis
hydrolysis to AMPM and adenosine
small, clear

29

Neuropeptides

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

excitatory and inhibitory
amino acids
synthesis and transport
proteases
large, dense-core

30

endocannabinoids

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

inhibits inhibition
membrane lipids
enzymatic modification of lipids
hydrolysis by FAAH
no vesicle

31

Nitric oxide

postsynaptic effect
precursors
rate limiting step in synthesis
removal mechanism
type of vesicle

excitatory and inhibitory
arginine
nitric oxide synthase
spontaneous oxidation
no vesicle

32

Acetylcholine metabolism in cholinergic nerve terminals

(mitochondria) glucose -> pyruvate -> acetyl CoA
(choline acetyl tranferase) acetyl CoA + Choline -> acetylcholine
(Vesicular ACh transporter) acetylcholine into vesicles
(synaptic cleft, acetylcholinersterase) acetylcholine -> acetate + Chooline
(Na+/choline symport;transporter) bring choline into the terminal to recycle

* Sarin - organophosphates : prevent breakdown of ACh resulting in paralysis

33

Myasthenia Gravis

results from decreased number of nAChRs
produce antibody to block activity of nAChRs - lose muscle coordination
MEPP amplitude also decreases as lacking nAChRs
autoimmune disease
treatment: cholinesterase inhibitor; keep profound number of ACh available

34

Glutamate

major excitatory neurotransmitter in CNS
ionotropic (NMDA, AMPA, Kainate) and metabotropic

35

NMDA

signal integration
synaptic plasticity
agonist - N-methyl-D-aspartate (NMDA)
neurotransmitter: glutamate
Mg2+ blocks during rest
- requires glutamate and depolarization to relieve the block
slower and longer than AMPA

36

AMPA

synaptic transmission
synaptic plasticity
agonist - alpha-amino-3hydroxyl-5-methyl-40isoxazole-proprionate
neurotransmitter: glutamate
faster and shorter than NMDA

37

Kainate

synaptic transmission
presynaptic modulation
agonist - kainic acid
neurotransmitter: glutamate

38

glutamate synthesisand cycling between neurons and glia

(glutaminase) glutamine->glutamate
(VGLUT; vesicular glutamate transporter) bring glutamate into vesicles
(synaptic cleft, EAAT; excitatory amino acid transporter) bring glutamate into terminal or glia
(glutamine synthetase) glutamate->glutamine

39

glutamate induced excitotoxicity

excessive activation of glutamate receptors
neuron death
post-synaptic cells; dendrites
ischemia (caused by stroke); increased glutamate in synapse after injury - decreased function of EAAT
& too much Ca2+ in cell

40

Proteolytic processing of the pre-propeptides

pre-propeptide
propeptide
active peptides

41

neuropeptides

3-36 amino acids
shortest: 3; thyrotropin releasing hormone (TRH)
longest: 36; Neuropeptide Y

42

ionotropic GABA receptors

Cl- selective channels
* other sites are allosteric for GABA binding
reversal potential for Cl- is usually lower than resting membrane potential --> usually inhibitory

43

synthesis, release, reuptake of inhibitory neurotransmitter, GABA

(mitochondria) Glucose->Glutamate
(glutamic acid decarboxylase & pyridoxal phosphate) glutamate->GABA
(VIATT)bring GABA into vesicles
(GAT, synaptic cleft) bring GABA into glial cell or terminal

44

endocannabinoid - inhibit inhibition

endougenous signaling molecules
synthetic THC - WIN 55,212 act as CB agonist
rimonabant act as antagonist
lipid precursors
inhibit GABAergic function - control GABA release
increased Ca2+ in post synaptic cell-> endoC production -> release from the cells -> diffuse back to presynapticcell through CB1 GPCR-> reduced release of GABA from nerve terminal
* voltage-gate Ca2+ channels or K+ channels
blocked by antagonizing CB1 receptors

45

GABA as an excitatory NT during development

E_Cl -50mV in developing brain, -70mV in adult brain - cf>-68mV resting membrane potential

Na+/K+/Cl- co-transporter is highly expressed in immature neuron -> higher intracellular concentration of Cl-
K+/Cl- co-transporter as maturation -> pump out Cl-; lowering intracellular concentration

46

Synaptogamin

red
interneurons labeled with MAP2 is green

47

Glutamatergic synapse

depolarization
NMDA and AMPA
nonselective
reversal potential near 0mV
EPSP generated

48

inhibitory synapse

GABAergic synapse
E_Cl typically -70mV (mature)
if E_Cl is above -50mV (immature), evoke depolarization; yet not enough to evoke AP; IPSP

49

Summation of postsynaptic potential

neurotransmitter release
receptor binding
ion channels open or close
conductance change causes current flow
postsynaptic potential changes
postsynaptic cells excited or inhibited
summation determines whether or not an action potential occurs