Neurochemistry

1. Lecture 9
1. D-serine neurotransmitter
2. Purinergic neurotranmitters
3. Melatonin
4. NAA & NAAG

2. Gliotransmitter?
3-hydroxy pyruvate

5. Schematic model of the proposed pathways mediating D-serine synthesis and release. Activation of
presynaptic neuron results in release of glutamate that binds to AMPA receptors on neighboring astrocytes
and causes release of D-serine. D-serine released from astrocytes binds to synaptic NMDAR-containing
GluN2A subunits. Extrasynaptic receptors containing GluN2B preferentially bind glycine instead of D-serine. SR
localized in neurons synthesizes D-serine from L-serine. L-serine is shuttled to neurons from astrocytes
through amino acid transporters (ASCT). SR is also responsible for the degradation of serine resulting in
production of pyruvate and ammonia.

6. FIGURE: Adenosine 5′-triphosphate. Adenosine is a purine nucleoside consisting of adenine and ribose. The addition of triphosphate generates ATP.
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

7. FIGURE: Purine release and metabolism. Although ATP is used as an energy source, it is also released as a signaling molecule. ATP is packaged into vesicles by vesicular nucleotide
transporter (VNUT), which provides an exocytotic release pathway. ATP can also be released by channels and transporters. In the extracellular space ATP is rapidly hydrolyzed to
adenosine by ectoenzymes. Purines have actions through P1, P2X and P2Y receptors. Adenosine is taken back up into cells via equilibrative or concentrative nucleoside transporters
(ENT, CNT) where it is metabolized to uric acid or via the action of adenosine kinase to AMP and ultimately to ATP. Metabolism through adenosine kinase dominates over adenosine
deaminase. Hypoxanthine can be metabolized to IMP and subsequently to AMP via the action of hypoxanthine-guanine phosphoribosyltransferase (HPGRT). Equilibrative transport of
adenosine allows bidirectional flow of adenosine and consequently the metabolic state of the cell to regulate extracellular adenosine. Under normoxic conditions, adenosine kinase
phosphorylates intracellular adenosine, causing a concentration gradient of adenosine into the cell and its uptake via ENT. However, under hypoxic conditions, or during periods of
metabolic demand, intracellular adenosine accumulation leads to its release through ENTs. (Blue). Mutations in adenosine deaminase are associated with changes in sleep,
presumably resulting from increased intracellular adenosine leading to release of this purine via ENTs and to extracellular adenosine accumulation. Increased expression of adenosine
kinase in rodent models of epilepsy lead to enhanced clearance of adenosine and removal of this natural anticonvulsant. Lesch-Nyhan Syndrome is an inherited disorder with
mutations in HPGRT.

8. FIGURE: The purinergic receptor family. The purinergic receptors are divided into two major families, the P1 (or adenosine receptors) and P2
receptors, which principally bind ATP, ADP, UTP or UDP. The P2Y14 receptor binds UTP sugars. P1 and P2Y receptors are coupled to GTP-binding
proteins. P2X subunits form trimeric ligand-gated ion channels.

9. TABLE: Subtypes of Adenosine Receptor, Selective Agonists and Antagonists

10. BOX FIG.: The role of the neuronal aspartate–glutamate carrier (aralar, AGC1) in N-acetylaspartate (NAA) formation and trafficking and providing acetyl groups
for synthesis of myelin lipids

13. FIGURE: The biosynthesis and catabolism of serotonin. Not only does 5-HT have important physiological effects of its own, but also it
is the precursor of the hormone melatonin. Note that in the pineal gland, which lies “outside” the blood–brain barrier, serotonin is
converted enzymatically to the hormone melatonin (5-methoxy-N-acetyltryptamine). The synthesis and secretion of melatonin is markedly
influenced by the light–dark cycle. A circadian rhythm of melatonin secretion persists in animals housed in continuous darkness. Thus,
melatonin synthesis is turned on by an endogenous “clock,” located within the SCN of the hypothalamus, with the daily rhythm normally
being entrained to the day–night, light–dark cycle (Reiter et al., 2010). Melatonin, which provides circadian and seasonal timing cues
through activation of G protein– coupled receptors (Dubocovich et al., 2003), has been implicated not only in the regulation of biological
rhythms, but also in sleep and affective disorders.
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.

16. AANAT = Arylalkylamine-N-
acetyltransferase (serotonin
acetyltransferase)
HIOMT = Hydroxyindole-O-
methyltransferase (acetylserotonin-
O-methyltransferase)
NAS = N- acetylserotonin;
Melatonin (MEL) = N- acetyl-5-
methoxytryptamine
• Pineal cyclicAMP levels mediated
mainly through noradrenaline β-
receptors are high in darkness and
low in light
• CyclicAMP increases AANAT levels
at the mainly level of mRNA
• Pineal microdialysis had shown
that a 1 min pulse of light gives a
rapid decrease in both
noradrenaline (returning to normal
in ~40 min) and melatonin
(returning to normal in ~2.5 h).