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Ch 6. neurotransmitter
NO,
Endocannabinoids-modified lipid
Nicotine receptor (nAChR)-brain/muscle
Non-selective channel
In brain-a(3):b(2)
Muscle -2a; b;g;d
Bungarotoxin-specific ligands for nAChR
Metabotrophic Receptor (mAChR)
* M2 and M4 is presynaptic auto-R
(N1)
(N2)
Neuron/KO-seizure/epilepsy
Neuron and heart, spinal cord/KOlearning and memory, LTP
Smooth muscle and gland/
Addiction –
opioid, cocain, marijuana, amphetamine, alcohol, nicotine
Withdrawal syndrome
Cocain-domapine level
morphine
mAch blockers (muscarine-mushroom)
Atropine- used to dilate the pupil
Ipratropium- asthma
Scopolamine-motion sickness
mAchR inhibits domapine function
Site
Predominant tone
Primary effects of ganglionic blockade
Arterioles
Sympathetic (adrenergic)
Vasodilation, increased peripheral blood flow, hy
potension
Veins
Sympathetic (adrenergic)
Dilation, pooling of blood, decreased venous ret
urn, decreased cardiac output
Heart
Parasympathetic (cholinergic)
Tachycardia
Iris
Parasympathetic (cholinergic)
Mydriasis
Ciliary muscle
Parasympathetic (cholinergic)
Cycloplegia (focus to far vision)
Gastrointestinal tract
Parasympathetic (cholinergic)
Reduced tone and motility of smooth muscle, co
nstipation, decreased gastric and pancreatic sec
retions
Urinary bladder
Parasympathetic (cholinergic)
Urinary retention
Salivary glands
Parasympathetic (cholinergic)
Xerostomia
Sweat glands
Sympathetic (cholinergic)
Anhidrosis
Tissue
Effects of ACh
Vasculature (endothelial cells)
Release of endothelium-derived relaxing factor (nitric oxid
e) and vasodilation
Eye iris (pupillae sphincter muscle)
Contraction and miosis
Ciliary muscle
Contraction and accommodation of lens to near vision
Salivary glands and lacrimal glands
Secretion—thin and watery
Bronchi
Constriction, increased secretions
Heart
Bradycardia, decreased conduction (atrioventricular block
at high doses), small negative inotropic action
Gastrointestinal tract
Increased tone, increased gastrointestinal secretions, relax
ation at sphincters
Urinary bladder
Contraction of detrusor muscle, relaxation of the sphincter
Sweat glands
Diaphoresis
Reproductive tract, male
Erection
Uterus
Variable, dependent on hormone influence
Neurotoxin
Myasthemia Gravis; autoimmune disease
-Muscle weakness
-autoAb against nAchR
-Treatment ; AchE inhibitor
Glutamate excitatory neuron
50% of brain neuron ; glutamine in glia is precusor of glutamate (that
cannot be penetrated BBB)
Sensory neuron
Motor coordination
Emotion.cognition (memory)
80% of enery is used for repolarization of glumatateneuron
Glutaminevesicle (VGLUT) or  GABA
EAAT; excitatory amino acid transporter (1-5)
EAAT1; astrocyte
EAAT2; principle transporter in forebrain
EAAT3; presynatic GABA
EAAT4: purkinje cell’s dentrite
EAAT5; renina
Post-synaptic density (PSD)
NMDA-1uM (Asp) channel for Ca2+, Na+ as well as K+
AMPA-400 uM (different sensitivity)
* GluR (900 AA vs 400AA ; GABA, Nicotinic R)
AMPA GluR2 KO-Seizure (embryonic lethal)
NMDA R KO- neonatal lethal (due to breath), in CNS, NMDA R is required for memory
Metabotrophic R-autoreceptor
Post-synaptic density (PSD)
AMPA R is differentially distributed at PSD (0-50)
2-amino-5-phosphono-valerate: specific antagonist for NMDA-R
GluR2 AMPA increase plasicity
NMDA-R: co-agonist glycine
GABA and Glycine
Local circuit interneuron
Inhibitory neuron
Glucose Krebs cycle
GAD (glumatic acid decarboxylase)
Cofactor of GAD; pyridoxal phosphate (vit B6)
VIATT packing protein
SSADH KO-lethal seizure
g-hydroxybutyrate data rape drug
By-product of GABA clearing
VIATT
Agonist –수면제 및 진정제
Benzodiazepine; 진정제
Chloride channel
Alcohol-activates ionotrophic GABA-R
mGABA R (GABAb)- K+ channel activation and C2+ channel blocking
Isoform
α1β2γ2
α2β3γ2
Relative a
bundanc
e
40%
15%
Location
Pharmacology/property
Most brain areas; hippocampal,
Common coassembly
cortical interneurons;
BZ-type I
cerebellar Purkinje cells
Zn-insensitive
Spinal cord motoneurons,
BZ-type II
hippocampal pyramidal cells
Moderately Zn-sensitive
α3βγ2/3
10%
Cholinergic, monaminergic neurons
BZ-type II, abecarnil-sensitive
α2βγ1
10%
Bergmann glia, thalamus, hypothalamus
BZ inverse agonist-enhanced
α5β3γ2/3
3%
Hippocampal pyramidal cells
BZ-type II, zolpidem-insensitive,
moderate Zn-sensitivity
α6βγ2
2%
Cerebellar granule cells
BZ agonist-insensitive, moderate
Zn-sensitivity
α6βδ
3%
Cerebellar granule cells
Insensitive to all BZ, GABA high aff
inity high Zn-sensitivity steroid-ins
ensitive
α4βγ
2%
Cortical, hippocampal pyramidal cells; striatum
BZ agonist-insensitive, low steroid
sensitivity
Insensitive to all BZ, GABA high aff
inity high Zn sensitivity, steroid-ins
ensitive
α4β2δ
4%
Thalamus, dentate granule cells
All other
11%
Throughout CNS
Glycine – spinal cord and brain stem (inhibitory neuron)
Removed by glycine transporter
Cl- channal
Catecholamine
NT and hormone
DCC: seratonin 형성에도 이용
Neuron and Kidney, blood vessel
에 분포
Kidney
DBH:Cu2+, vesicle of Cateolamine
Co-released with Catecholamine; in cytosol
Neuron and adrenal gland
Corticoid of Adrenal gland
Dopamine-coordination of movement, PD, motivation, reward, reinforcement
NE; sleep and wakefulness, attention, feeding behavior, cleared by NET
Epinephrine-unknown function in brain
All receptor is metabotrophic receptor (G-coupled )
Increase in PD
*VMAT2: KO-lethal
* VMAT2 disorder: bipolar disorder- LiCl
cytosol
cytosol
MAO
ATP-dependent proton pump (SERT)
uptake
Dopamine in vesicle (ATP and chromogranins)
VMAT2
vesicle
Clearing in cytosol
DBH
Reserpine
(혈압강하제,
진정제) NOR in vesicle
MAO
PNMT
(cytosol)
MAO
corticosteroid
Ca2+
release
Nor, ATP, Chromogranin
DBH
MAO and COMT: clearing of cathecholamine
MAO;Mito-outer Memb; eliminates free, vesicle-unpacking Cathecholamine
MAO-A; - Nor and seratonine; selective inhibitor- Clorglycine (우울증 치료제)
MAO-B: broad spectrum; inhibitor-deprenyl (파킨슨 치료제)
MAO in GI tract: protecting amine circulation
* 적포도주, 치즈, 청어
COMT – wide expressed enzyme, Mg2+
COMT KO- dopamine level increase
In Human, SNP of COMT is related with schizophrenia
Inhibitors of MAO or COMT (phenelzine, tranylcypromine) are used for antidepressants
* DAT (domain transporter in synaptic cleft) blocker  cocaine
Table 12-1. Studies with Knockout Mice
Tyrosine hydroxylase
Not viable
[ 32]
Dopamine hydroxylase
Not viable
[ 33]
Dopamine transporter
Hyperlocomotion, no effect of MPTP or
psychostimulants
[ 34]
Vesicular transporter
Not viable
[ 35]
α2B-Adrenergic receptor
Apparently normal
[ 36]
β1-Adrenergic receptor
Most die prenatally, survivors have altered
cardiovascular responses
[ 37]
β3-Adrenergic receptor
Altered leptin and insulin concentrations after
agonist treatment
[ 38]
[ 39]
Dopamine 1 (D1) receptor
Lack responses to agonists, hyperlocomotion,
altered striatal peptides
[ 40]
[ 41]
Dopamine 2 (D2) receptor
Impaired movements
[ 42]
Dopamine 3 (D3) receptor
Hyperlocomotion
[ 43]
See Chap. 40 for a discussion of knockout mice. MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Table 12-2. Properties of Amine Transporters
NET
VMAT-2
DAT(코카인)
Mechanism
NaCl-dependent
NaCl-dependent
H+-dependent
Transmembrane segments
12
12
12
Amino acids
617
620
742
Chromosome
16
5
10
Blockers
Nisoxetine, desipramine
GBR12909, RTI-121
Reserpine, tetrabenazine
The neuronal membrane norepinephrine transporter (NET), the dopamine transporter (DAT) and the vesicular membrane transporter (VMAT-2),
which is the same in all catecholamine-containing neurons, have similar numbers of predicted transmembrane segments. They have different
numbers of amino acids, pharmacological properties and chromosomal localizations.
•Volume transmission; different reuptake ability
•MPP+ (mercaptopyrazide pyrimidine)-selective toxicity on
dopaminergic neuron, uptaken by transporter
Table 12-3. Properties of Cloned Dopamine Receptor Subtypes
Auto-receptor
NE and epinephrine receptor
a1, a2, and b
autoreceptor
Seratonin and histamine
5-HT: serum factor-muscle contraction
식욕, 감정, 운동성, 인지력등에 관여
Location: platelet, GI tract, brain
5-HT cannot pass BBB
LSD (Lysergic acid diethylamide) is antagonist against 5-HT
정신분열증, 우울증, 흥분증
각성작용에 중요
Serotonergic neuron 은 1-5번/sec로 활성화
이보다 늦어지면 수면 (slow wave sleep)
REM 시 활성은 거의 없음
각성시 증가 그러나 긴장과는 무관
DET, DMT- 마약류
Table 13-1. Classification of Serotonergic Cell Body Groups
According to Dahlstrom and Fuxe and Corresponding Anatomical
Structure
Groups of serotonin-containing cell
bodies
Anatomical structure
B1
Raphe pallidus nucleus, caudal ventrolateral medulla
B2
Raphe obscurus nucleus
B3
Raphe magnus nucleus, rostral ventrolateral medulla, lateral paragigantocellular reticular
nucleus
B4
Raphe obscurus nucleus, dorsolateral part
B5
Median raphe nucleus, caudal part
B6
Dorsal raphe nucleus, caudal part
B7
Dorsal raphe nucleus principal, rostral part
B8
Median raphe nucleus, rostral main part; caudal linear nucleus; nucleus pontis oralis
B9
Nucleus pontis oralis, supralemniscal region
Modified from [ 3] with permission.
•Synthesis of 5-HT is
dependent on frequency
and extracellular Ca2+
Blood
Rate limiting step
•Plasticity; damage of
Seratonergic neuron can
increase 5HT synthesis in
neuro-terminus
AADC=DOPA DC
*pH, co-factor
Neutral AA
transporting
System
(F, M, L)
Food
•AA의 종류와 무관하
게 transporting
•식이요법 가능
SERT
SBP, Fe2+
•Reserpine/tetrabenazine: inhibitor of VMAT2 -> deplete Cathecholamine and 5-HT
•SERT transport 5-HT from cytosol to vesicle and from extracellular space to cytoplasm
•SERT: brain specific expression, not glia
* Astrocyte can re-uptake seratonine
•Re-uptake of seratonine; Na/Cl dependent, Temp dependent
•MDMA (ecstasy)
•Fenfluramine- 식욕 억제제
•5-HT1b- 식사량 조절 /5-HT2C-식사속도
•Sert structure; 68kDa, 12 Transmemb domain
•Brain specific expression (serotonergic neuron)
50% homology
•Net can re-uptake 5-HT
•(functional redundancy)
•PKA, PKC are kinases
*
Cocaine is non-selective inhibitor for SERT, NET, DAT
•N or C-terminus are not essential for substrate-specificity (chimeric protein)
Eating disorder, anxiety, obsessive-compulsive disorder
obsessive-compulsive disorder
Long term SSRI reduces SERT
Short term increase SERT by autoreceptor
SERT is regulated by Estrogen, Ca2+, PKC, cAMP
여성 우울증
SNP of SERT
Elimination of 5-HT by MAO-A
Human; B>A
Rat : A>B
In human 5-HT is more stable and protected from dopamine-packing
MAO-A KO mice are aggressive
Clinically, MAO-I and SSRI is effective in depression
Volume transmission
5-HT 식욕억제 (포만감을 유도)
Table 13-2. Serotonin Receptors Present in the Central Nervous System
Receptora
Human locus
5-HT1A
5q11.2–13
Hippocampus, amygdala, septum, entorhinal cortex, hypothalamus, raphe nuclei
(Azapirones; agonist; anti-anxiety, depression)
Inhibition of adenylyl cyclase, opening of K+
channels
5-HT1Dα
1p34.3–36.3
Not distinguishable from 5-HT1Dβ
Inhibition of adenylyl cyclase
5-HT1Dβ
6q13
Substantia nigra, basal ganglia, superior colliculus
Inhibition of adenylyl cyclase
5-ht1E
?
?
Inhibition of adenylyl cyclase
5-ht1F
3p11
Cerebral cortex, striatum, hippocampus, olfactory bulb
Inhibition of adenylyl cyclase
5-HT2A
13q14–21
Claustrum, cerebral cortex, olfactory tubercle, striatum, nucleus accumbens
Stimulation of phosphoinositide-specific
phospholipase C, closing of K+ channels
5-HT2B
2q36.3–37.1
?
Stimulation of phosphoinositide-specific
phospholipase C
5-HT2C
Xq24
Choroid plexus, globus pallidus, cerebral cortex, hypothalamus, septum, substantia nigra,
spinal cord (rate of eating)
Stimulation of phosphoinositide-specific
phospholipase C
5-HT3
?
Hippocampus, entorhinal cortex, amygdala, nucleus accumbens, solitary tract nerve,
trigeminal nerve, motor nucleus of the dorsal vagal nerve, area postrema, spinal cord
Ligand-gated cation channel
5-HT4
?
Hippocampus, striatum, olfactory tubercle, substantia nigra
Stimulation of adenylyl cyclase
5-ht5A
7q36
?
Inhibition of adenylyl cyclase
5-HT5B
2q11–13
?
?
5-ht6
?
?
Stimulation of adenylyl cyclase
5-HT7
10q23.3–24.3
Cerebral cortex, septum, thalamus, hypothalamus, amygdala, superior colliculus
Stimulation of adenylyl cyclase
a
Distribution
Lower-case appellations are used in some cases because the functions mediated by these receptors in intact tissue are presently unknown.
Effector mechanism
5-HT1A- feeding, sexual behaviour, body temp
5-HT1B, 5-HT1D-> auto-receptor (inhibition adenyl cyclase)
Agonist; sumatriptan, zolmitriptan-> 편두통에 사용
5-HT2A-antagonist; 정신병치료제
Histamine; awakefulness
Histamine in Neuron is revealed by Mast cell deficient mice
Histamine in brain
Brain and dural mast cell- located in near –vessel- regulates blood pressure, sensory nerve
Motion sickness (H1 receptor), vesicular system
GI tract-H2 receptor
Cerebrovascular endothelial cell also synthesis and store Histamine
Mast cell near brain can regulate neuron and involve in multiple sclerosis and AD
Hypothalamus and SN
Co-localized with GABA, neuropepide * co-tramsmitter
Histaminergic modulation of transmitters
Transmitter
Transmitter parameter
Transmitter modulation of histamine
Receptor
Effect
Histamine parameter
Receptor
Effect
Acetylcholine
Release
H3
↓a
Release
M1
↓
Acetylcholine
Release b
H2
↑
Release b
M1
↓
Acetylcholine
Turnover
muscarinic
↓
Acetylcholine
turnover
nocotinic
↓
CGRP, substance P
Release c
H3
↓
Dopamine
Release
H3
↓
Release b
D2
↑
Dopamine
DOPAC levels
H1
↑d
Release b
D3
↓
GABA
Release b
GABAA,B
↓
GABA
Turnover
?
↓
Glutamate
Release b
NMDA
↑
Release
α2
↓
Norepinephrine
Release
H3
↓
Norepinephrine
Release b
H1
↑
Norepinephrine
Turnover
H1
↑
Opioids
release
κ
↓
Opioids
turnover
κ
↓
Opioids
release
m
↑
Opioids
turnover
m
↑
Serotonin
Release
H3
↓
Release b
5HT2C/2A
↑
Serotonin
5-HIAA levels
H1
↑e
Turnover
5HT1A
↓
Experiments investigating the interactions between brain histamine and other transmitters are summarized. Unless otherwise specified, “release” experiments
were performed in vitro with brain slices or synaptosomes.
a Inhibition by H receptor may not be direct.
3
b Release measured by in vivo techniques.
c Release from isolated perfused heart.
d Some effects of histamine on dopaminergic parameters are found to depend on noradrenergic activity.
e Exogenous, but not endogenous histamine increased 5-hydroxytryptamine (5-HT) metabolite levels.
CGRP, calcitonin gene-related peptide; DOPAC, 3,4-dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindoleacetic acid; NMDA, N-methyl-d-aspartate. See [37, 43,
44] for references.
Co-transmitter with galanin, GABA, adenosine
Galanin
Histamine release in presynapse
GABA
Seratonin, Acethylcholine
* Neuropeptide (galanin) suppresses Histamine release
* Histamine is not target of MAO
•pyridoxal-5-phosphate(co-factor)
•Similar to DDC
* IAA is agonist for GABA
* HMT is dominant in CNS
Histidine decarboxylase (HDC) is key enzyme
Histamine can not penetrate BBB
HDC is regulated by hormone and neurofactor
PKA is key regulator
no end product inhibition by histamine
Feedback loop by autoreceptor (H3)
Histamine storage into vesicle is achieved by VMAT2
No re-uptake system in neuron
Re-uptake by astrocyte HMT in glia (clearing)
MAO inhibition did not alter histamine
Characteristics
H1
H2
H3
Cloned?
Yes
Yes
No
Gene localization (mouse)
Chromosome 6
Chromosome 13
Chromosome 2
Effectorsa
PI-PLC: ↑ IP3 [↑Ca2+, ↑cGMP]
↑ cAMP
Unknown
PI-PLC: ↑ DAG [↑PKC]
↑ PI-PLC: Ca2+, IP3e
PI-PLA2: ↑ AA, ↑ TXA2
↓ AAe
Excit: ↓ K+ (mammals)
Excit: ↓ IkCa2+
Conductances
(recent H4 also isolated)
Inhib: ↑ K+ (?)
↑ Na+ (invertebrates)
Selective agonists
Inhib: ↑ IkCa2+
Inhib: ↓ Cl− (?)
2-Thiazolylethylamine,
Impromidine
R-α-Methylhistamine,b
2-phenylhistamine
amthamine
imetit,
immepipb
Antagonists
Radioligands
Pyrilamine (mepyramine),b
Ranitidine
Thioperamide,b
terfenadine
Zolantidineb
clobenpropitb
3H-Pyrilamine,
125I-Iodoaminopotentidine
3H-Nα-Methylhistamine,
125I-Iodobolpyramine
125I-iodophenpropit,
125I-iodoproxyfan
CNS distributiond
Cerebellum, thalamus, hippocampus
Cerebral cortex, striatum, nucleus
accumbens
Striatum, nucleus accumbens, cerebral cortex,
substantia nigra
Localizationc
Neurons, astrocytes, blood vessels
Neurons, astrocytes, blood
vessels
Presynaptic (auto) and postsynaptic
The characteristics of the three major classes of histamine receptors are summarized. Question marks indicate suggestions from the literature that have not been
confirmed. AA, arachidonic acid; TXA2, thromboxane A2; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PI-PLC, phosphoinositidespecific phospholipase C; IkCa2+, calcium-activated potassium current..
b Has brain-penetrating characteristics after systemic administration.
c All three receptors may exist in non-neuronal brain tissue as well.
d Distribution in guinea pig (H and H ) and rat (H ) brain. For the H receptor, distribution is very different across species.
1
2
3
1
e Contradictory findings have been reported.
a
Auto-R, constitute active
MAPK
memory
Histamine is neuromodulator
Histamine
Non synaptic release- diffuse /slow transmission
Attention by sensory input
Awakfulness
Inhibition of TM-진정효과
Pain relief
Ischemic protection
glutamate
Histamine
NMDA
D2-dopa (auto-R)
H3-R (auto-R)
H1 or 2-R (auto-R)
Acetylcholine
Dopamine
Norepinephrine
Seratonine
neuropeptide
Acetylcholine
Dopamine
Norepinephrine
Seratonine
neuropeptide
dopamine
m opoid
Seratonine-R
*H1 ko mouse- locomotion, exploration behavior defect
GABA
Food uptake
Water uptake
seratonine
histamine
sleep
Leptin
H1
seizure
Purinergic systems
Voltage-gated ion channel
ATP is co-localized in secretory vesicles (dopamine eg)
Co-released with acethylcholine (1; 10=ATP; Ach), norepinephrine
ATP is also released from endothelial cells, epithelial cells or others in response to
Hypoxia, mechanical stress
Extracellular ATP is converted rapidly by ectoenzymes
In normal condition
ATP ; AMP =50:1 (inner cell)
5-nucleotidase is critical and activated by PKC
Neuroprotective role of
nucleotidase and ectocyclic
AMP phosphodiesterase
glutamate
B-adnergeric R
cAMP
Ca2+
release
ectocyclic AMP
phosphodiesterase
AMP
nucleotidase
adenosine
Enzyme
Substrate
Inhibitor
ATP diphosphohydrolase (CD39)
ATP, ADP
ARL67156 (* active B cell marker)
Diadenosine pholyphosphatase
ApnA
Suramin a
5′-Nucleotidase (CD73)
AMP (ATP:AMP ratio )
AOPCP
Nucleoside transporter
Adenosine
Dipyridamole, NBTI, mioflazine
Adenosine deaminase
Adenosine
EHNA, 2-deoxycoformycin
Adenosine kinase
Adenosine
5′-Iodotubercidin, 5′-deoxy-5′amino-adenosine
Xanthine oxidase
Hypoxanthine, xanthine
Allopurinol, CMTA
Nucleoside phosphorylase
Inosine
8-Aminoguanosine
a Suramin
also is an inhibitor of P2 receptors.ARL 67156, 6-N,N-diethyl-d-β,γ-dibromomethylene ATP; AOPCP, α,βmethylene-adenosine diphosphate; NBTI, nitrobenzylthioinosine; ApnA, diadenosine polyphosphate (n = 3–6); EHNA,
erythro-9-(2-hydroxy-3-nonyl)adenine; CMTA, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
Adenosine; not classical NT; no quanta release; neuromodulator
Transporting; rCNT1 (Na+-nucleoside cotransporter); pyrimidine, rCNT2; purine
Inosine (UTP); neuroprotective effect
IschemiainosineA3 (receptor)anti-inflammation (Macrophage inhibition)
Caffeine ( coffee, tea, chocolate) P1 receptor blocker
Endothelial cell, platelet
Purkinje cell
Glutamate release
vasodilation
GTP binding region
Receptor/(accession #) a
A1 (S45235)
Effector b
Adenylyl cyclase (−)
Agonist
Antagonist
CPA
WRC-0571, CPX, CVT-124
K+ channels (+)
Ca2+ channels (−)
PI-PLC (+ via βγ)
A2A (S46950)
Adenylyl cyclase (+)
CGS21680
ZM241385, SCH58261, CSC
A2B (M97759)
Adenylyl cyclase (+)
None
Enprofylline
IB-MECA
L-249313
NECA
SPT
PI-PLC (+ via αq)
A3 (L22607)
Adenylyl cyclase (−)
PI-PLC (+ via βγ)
Nonselective ligands
a Genebank
accession numbers are for human clones.
phosphoinositide-specific phospholipase C; βγ and αq, subunits of GTP-binding proteins activated by these
receptors.CPA, N6-cyclopenthyadenosine; WRC-0571, C8-(N-methylisopropyl)-amino-N6-( 5′-endohydroxy)-endonorbornan-2yl-9-methyladenine; CPX, 1,3-dipropyl-8-cyclopentylxanthine; CVT 124, S-1,3-dipropyl-8[2-(5,6-eoxynorbornyl)]xanthine;
CGS21680, 2-[4-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine; ZM241385, 4-(2-[7-amino-2-[2-furyl][ 1, 2,
4]triazolo[2,3-α][ 1,3, 5] triazin-5-yl-aminoethyl)phenol; SCH58261, 5-amino-7-(2-phenylethyl) -2-(2-furyl)-pyrazolo [4,3epsilon]-1,2,4-triazolo[1,5-c]pyrimidine; CSC, 8-(3-chlorostyryl)-caffeine IB-MECA, N6-(2-iodo)benzyl-5′-Nmethylcarboxamidodo adenosine; l-249313, 6-carboxymethyl-5,9-dihydro-9-methyl-2-phenyl-[ 1, 2, 4]-triazolo[5,1-α][ 2,
7]naphthyridine; NECA, 5′-N-ethylcarboxamidoadenosine; SPT, p-sulfophenyltheophylline. Xanthines block P1 but not P2
receptors.
b PI-PLC,
Receptor
Accession # b
Transcript location
P2X1
X83688
P2X2
—
P2X3
Y07683
A subset of small cells of sensory neurons
P2X4
Y07684
Widespread in brain and spinal cord
P2X5
U49395
Proprioceptive neurons of mesencephalic trigeminal nucleus, sensory ganglia
P2X6
—
P2X7
Y09561
Macrophages
P2Y1
Z49205
Telencephalon, diencephalon, mesencephalon and cerebellum
P2Y2
U07225
Found in pituitary but not in human brain
P2Y4
X91852
Not detected in human brain
P2Y6
X97058
Not detected in human brain
a From
Large motor neurons of the spinal cord
Sensory and autonomic ganglia, adrenal medulla, dorsal and ventral horns of the
spinal cord, thalamus, hypothalamus, preoptic area, red nucleus, oculomotor
nucleus, locus ceruleus and dorsal motor nucleus of vagus
Widespread in brain, spinal cord and sensory ganglia
[ 1] with permission.
accession numbers of human clones.
b Genebank
A1
A2
Adenosine; inhibitory role by A1 – presynaptic location K+ channel
예외적 excitatory role –glutamate release
Opiates induce Adenosine release/ adenosine antagonist block the opiate-effect
•Alcohol block adenosine transport
•진통효과
•ATP on glutamate is also important for learning and memory
Neuropeptide
Vasopression; 9 AA, hypothalamus blood
CCK
Substance P
Neuropeptide system ; hydra, yeast
Isolation of neuropeptide extract, hybridization, DD, orphan receptor
Difference between classic neurotransmitter
1.
2.
3.
4.
5.
Low conc and higher affinity to receptor
Synthesis in soma and post-translational modification (multicopies; eg FMRF-NH3; 29 copies)
No-re-use and no-re-uptake system
Different secretion site
LDCV contains ATP