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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 Glutaminevesicle (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 IschemiainosineA3 (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