(neuro)

Neurotransmitters and other chemical signalling agents


Small-molecule neurotransmitters

Acetylcholine (ACh)

Precursors:
Choline and acetyl-CoA
Synthesising enzymes:
Choline acetyl transferase
Metabolising enzymes:
Acetylcholinesterase
Metabolite:
Choline and acetate
Receptor subtypes Agonists Antagonists Second messenger
M1 muscarinic Methacholine Pirenzepine, telenzepine PI
M2 Methacholine Himbacine, methoctramine (-ve)cAMP, (+ve)gK+
M3 Methacholine Hexahydrosila- difenidol PI
M4 M5 MB Methacholine Tropicamide (-ve)cAMP PI
Nicotinic (neuronal/ ganglion type) Dimethylphenyl- piperazinium, nicotine mecamylamine, hexamethonium ((+)tubocurarine blocks channel) (+ve)g(cation)
Nicotinic (muscle type) Suxamethonium (also causes depolarisation block) α-bungarotoxin, (+)tubocurarine (decamethonium blocks channel) (+ve)g(cation)

Adenosine (P1 purinoceptors)

Precursors:
Mainly AMP (from released ATP)
Synthesising enzymes:
Mainly 5´-nucleotidase
Metabolising enzymes:
Adenosine deaminase
Metabolite:
Inosine
Receptor subtypes Agonists Antagonists Second messenger
A1 CPA, R-PIA, GR 79236 8PT, DPCPX (-ve)cAMP
A2A CGS21680, CV-1808 8PT, CGS 15943 (+ve)cAMP
A2B Metrifudil 8PT (+ve)cAMP
A3 MB R-PIA, NECA none (-ve)cAMP

ATP (P2 purinoceptors)

Precursors:
Normal cellular constituent; formed from ADP
Synthesising enzymes:
Phosphorylases
Metabolising enzymes:
Phosphatases
Metabolites:
ADP, AMP, adenosine, inosine
Receptor subtypes Agonists Antagonists Second messenger
P2X β-γ-Me-ATP α-β-Me-ATP (desensitises) suramin (+ve)g(cation) or (up)gCa2+
P2Y ADP-β-F, 2-Me-S-ATP Reactive blue 2, suramin PI, (+ve)gK
P2T (platelet) ADP Suramin, AMP (-ve) cAMP, (+ve)g(cation)
P2Z (mast cell) ATP4- none ?
P2U UTP none PI

Monoamines (biogenic amines)

Norepinephrine (Noradrenaline; NA) and Epinephrine (Adrenaline; AD)

Precursors:
L-Tyrosine (a) → L-DOPA, (b) → dopamine, (c) → noradrenaline, (d) → adrenaline
Synthesising enzymes:
(a) tyrosine hydroxylase, (b) L-aromatic amino-acid decarboxylase, (c) dopamine-β-hydroxylase, (d) phenylethanolamine-N-methyl transferase
Metabolising enzymes:
MAO and COMT
Metabolites:
Vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG)
Receptor subtypes Agonists Antagonists Second messenger
α(1A) Phenylephrine Prazosin, (+)-niguldipine PI
α(1B) Phenylephrine Prazosin, CEC PI
α(1C) Phenylephrine Prazosin, CEC PI
α(2A) Oxymetazoline Yohimbine, fluparoxan (-ve)cAMP, (down)gCa(2+), (down)gK+
α(2B) UK14304 Prazosin, ARC 239 (-ve)cAMP, (down)gCa(2+)
α(2C) UK14304 Yohimbine (-ve)cAMP
β(1) Xamoterol, RD363 Practolol, atenolol, CGP20712A (+ve)cAMP
β(2) Salbutamol, salmeterol, procaterol ICI 118551 (+ve)cAMP
β(3) BRL 37344 BRL 35135 cyanopindolol (+ve)cAMP

Dopamine (DA)

Precursors:
Tyrosine (a) → L-dihydroxyphenylalanine (L-DOPA), (b) → dopamine
Synthesising enzymes:
(a) Tyrosine hydroxylase; (b) L-aromatic amino-acid decarboxylase (DOPA decarboxylase)
Metabolising enzymes:
MAO and catechol-O-methyl transferase (COMT)
Metabolite:
3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)
Receptor subtypes Agonists Antagonists Second messenger
D1 SKF 38393 Sch 23390 (+ve) cAMP
D2 Quinpirole Sulpiride (+ve)gK+
D3 7-OH-DPAT AJ-76 ?
D4 Dopamine Clozapine ?
D5 Dopamine Sch 23390 (+ve)cAMP

5-Hydroxytryptamine (5-HT; serotonin)

Precursors:
Tryptophan (a) → 5-hydroxytryptophan (b) → 5HT
Synthesising enzymes:
(a) Tryptophan hydroxylase, (b) 5HTP decarboxylase
Metabolising enzymes:
Monoamine oxidase (MAO)
Metabolite:
5HIAA
Receptor subtypes Agonists Antagonists Second messenger
5HT(1A) 8-OH-DPAT Way 100135, SDZ 216-525 (-ve) cAMP
5HT(1B) CP 93129 Cyanopindolol (-ve) cAMP
5HT(1C) now re-classified as 5HT(2C)
5HT(1D) 5CT, sumatriptan Methiothepin, methysergide (-ve) cAMP
5HT(1D-α) MB
5HT(1DB) MB (human homologue of the rodent 5HT1B receptor)
5HT(1E-α) MB (-ve) cAMP
5HT(1EB) MB (-ve) cAMP
5HT(1F) MB (-ve) cAMP
5HT(2A) (old 5HT(2)) DOI Ketanserin PI
5HT(2B) (rat fundus) DOI Ketanserin PI
5HT(2C) (old 5HT1C) mCPP Mesulergine PI
5HT(3) 2-Me-5HT Ondansetron, granisetron (+ve)g(cation)
5HT(4) 5MeOTrp, cisapride GR 113808 (+ve)cAMP
5HT(5) MB (binds bufotenine)

Histamine (HA)

Precursors:
Histidine
Synthesising enzymes:
Histidine decarboxylase
Metabolising enzymes:
Histamine-N-methyl transferase, histaminase, etc.
Metabolite:
Methylhistamine, IAA and others
Receptor subtypes Agonists Antagonists Second messenger
H(1) 2-thiazolyl- ethylamine Mepyramine PI
H(2) Dimaprit Ranitidine, cimetidine (+ve)cAMP
H(3) (R)-α-methyl histamine Thioperamide ?

Excitatory amino acids (EAA)

Glutamate (Glu) (and Aspartate)

Precursors:
None
Synthesising enzymes:
None
Metabolising enzymes:
Glutamate transaminase (uptake is more important)
Metabolite:
Glutamine
Receptor subtypes Agonists Antagonists Second messenger
NMDA (subtypes MB) NMDA AP5, CPP, CGP37849 (MK801 is a channel blocker, PCP is non-competitive) (+ve)g(cation)
AMPA (subtypes MB) AMPA, quisqualate NBQX, NQX DNQX (+ve)g(cation)
Kainate (subtypes MB) Kainate, domoate NBQX, NQX DNQX (+ve)g(cation)
Metabotropic (subtypes MB) 1S,3R-ACPD, ibotenate None PI

Inhibitory amino acids (IAA)

γ-Aminobutyric Acid (GABA)

Precursors:
Glutamate
Synthesising enzymes:
Glutamic acid decarboxylase (GAD)
Metabolising enzymes:
GABA transaminase
Metabolite:
Succinic semialdehyde
Receptor subtypes Agonists Antagonists Second messenger
GABAA Muscimol, THIP, isoguvacin Bicuculline, picrotoxin (+ve)gCl
GABAB Baclofen, CGP 97541 2-OH-Saclofen, CGP 35348 (-ve)gK+, (-ve)gCa2+, (-ve)cAMP
Benzodiazepine site on GABAA receptor Diazepam (DMCM is an inverse agonist) Flumazenil Enhances (+ve)gCl- by GABA

Glycine (Gly)

Precursors:
None
Synthesising enzymes:
None
Metabolising enzymes:
None (uptake is more important)
Metabolite:
None
Receptor subtypes Agonists Antagonists Second messenger
Glycine Glycine Strychnine (+ve)gCl-
Allosteric site on NMDA receptor Glycine 7-chloro-kynurenate n/a

Large-molecule neurotransmitters (neuropeptides) and other substances

Angiotensin II (AT II)

Precursors:
Angiotensin I
Synthesising enzymes:
Angiotensin converting enzyme (ACE)
Metabolising enzymes:
Aminopeptidase
Metabolite:
Angiotensin III
Receptor subtypes Agonists Antagonists Second messenger
AT1 Angiotensin II,III Losartan (DuP753), GR 117289 PI, (-ve)cAMP
AT2 Angiotensin II,III PD 123177, PD 123319, CGP42112 (-ve)cGMP

Bradykinin (BK)

Precursors:
Kininogens
Synthesising enzyme:
Kallikrein
Metabolising enzyme:
ACE, kininase I (carboxypeptidase-N)
Metabolites:
Des-Arg9-bradykinin, other fragments
Receptor subtypes Agonists Antagonists Second messenger
B1 Des-Arg9-BK Des-Arg9, Leu8-BK Des-Arg10-HOE140 ?
B2 Hyp9,Tyr(Me)8-BK NPC567, HOE140, NPC349 PI

Cholecystokinin (CCK) (and Gastrin (G))

Precursors:
Preprocholecystokinin
Synthesising enzymes:
Post-translational peptidases
Metabolising enzymes:
Endopeptidase EC 24:11
Metabolite:
Peptide fragments
Receptor subtypes Agonists Antagonists Second messenger
CCK(A) A71378 Devazepide, lorglumide PI
CCK(B) CCK4 L365260, PD134308 ?
Gastrin * G17 L365260 PI
* may be identical to CCK(B)

Enkephalin (met- and leu-) and Dynorphin

Precursors:
Proenkephalin and prodynorphin
Synthesising enzymes:
Peptidases
Metabolising enzymes:
Enkephalinase (EC 24:11) and other peptidases
Metabolite:
Peptide fragments
Receptor subtypes Agonists Antagonists Second messenger
μ-opoid DAGOL (DAMGO) Naloxone (-ve)cAMP, (+ve)gK+
δ-opoid DPDPE Naltrindol (-ve)cAMP, (+ve)gK+
κ-opoid U69593, CI 977, dynorphin Norbinaltorphimine (-ve)gCa2+

Endothelin (ET)

Precursors:
preproET-1 etc.
Synthesising enzymes:
“endothelin converting enzyme”
Metabolising enzymes:
not known
Receptor subtypes Agonists Antagonists Second messenger
ET(A) ET-1, ET-2 FR139317, BQ123 PI
ET(B) Sarafotoxin S6C, [Ala(1),(3),(11),(15)] ET-1, BQ 3020 IRL 1038 PI
ET(C) MB

Nitric Oxide (NO; formerly EDRF)

Precursors:
L-arginine
Synthesising enzymes:
NO synthase
Metabolising enzymes:
none: diffusion and spontaneous breakdown
Metabolite:
NO(2)-, NO(3)-
NO has no conventional receptor, but it activates guanylate cyclase directly. It can be generated by glyceryl trinitrate or sodium nitroprusside. The synthetic enzyme can be inhibited by L-NMMA and L-NAME. Three NO synthases have been cloned, of which one (in macrophages) is\inducible, and two (in brain and endothelium) are constitutive.

Prostanoids (Prostaglandins, prostacyclin and thromboxane)

Precursors:
rachidonic acid (i.e. eicosatetraenoic acid; 2-series prostanoids), eicosatri- and eicosapentaenoic acids
Synthesising enzymes:
Prostaglandin synthetase (cyclooxygenase), PGI2 synthase, TX synthase.
Metabolising enzymes:
15-hydroxyprostaglandin dehydrogenase, PG-9-keto-reductase
Metabolites:
large number of oxidised metabolites
Receptor subtypes (most potent natural prostanoid) Agonists Antagonists Second messenger
DP (PGD(2)) BW245C, ZK110841 BWA868C, AH6809 <87>cAMP
EP (PGE(2)), subdivided as shown:
EP(1) sulprostone, iloprost AH6809, SC-19220 PI
EP(2) AY23626, butaprost, rioprostil none <87>cAMP
EP(3) sulprostone AY23626, rioprostil, enprostil, GR 63799 none PI, <51>cAMP
FP (PGF(2-α)) fluprostenol, cloprostenol none PI
IP (PGI(2)) iloprost,cicaprost none <87>cAMP
TP (TXA(2)) U-46619, STA2, EP171 GR32191, EP092, BM13505, SQ28668 PI

Substance P (SP) and Neurokinins A and B (NKA, NKB)

Precursors:
Preprotachykinins
Synthesising enzymes:
Peptidases
Metabolising enzymes:
ACh-esterase, EC 24.11
Metabolite:
Peptide fragments
Receptor subtypes Agonists Antagonists Second messenger
NK(1) SPOMe, GR 73632, Sar9Met(O2)11SP GR82334, RP67580, CP-99994 PI
NK(2) GR 64349 L-659877, SR48968, MEN10207, GR94800 GR100679 PI
NK(3) Senktide GR138676 PI

Other neurotransmitter substances

Neurotransmitter Abbreviation
Antidiuretic hormone (vasopressin) ADH
Atrial natriuretic peptide ANP or ANF
Bombesin
Calcitonin-gene-related peptide CGRP
Corticotrophin-releasing factor CRF
Galanin --
Leukotriene LT
Luteinising hormone releasing hormone LHRH
Melatonin --
Neuropeptide Y NPY
Neurotensin NT
Oxytocin --
Pancreatic polypeptide (human) (h)PP
Peptide YY PYY
Platelet aggregating factor PAF
Somatostatin SS or SRIF
Taurine --
Thyrotropin-releasing hormone TRH
Vasoactive intestinal polypeptide VIP

NB: (+ve) indicates increase; (-ve) indicates decrease.


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