Neurotransmitter in biochemistry cns portion.
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Neurotransmitters in Biochemistry - CNS
(Source: Basic Medical Biochemistry - A Clinical Approach, 6e, Chapter 46)
Overview
Neurotransmitters fall into two structural categories:
- Small nitrogen-containing molecules - glutamate, GABA, glycine, acetylcholine, dopamine, norepinephrine, serotonin, histamine, epinephrine, aspartate, and nitric oxide
- Neuropeptides - synthesized in the CNS (endorphins, growth hormone, TSH, etc.) - often cleaved from larger precursors
General features common to small nitrogen-containing neurotransmitters:
- Synthesized from amino acids, glycolysis/TCA cycle intermediates, and O2 in the cytoplasm of the presynaptic terminal
- Rate of synthesis is regulated to match the neuron's firing rate
- Stored in vesicles via an ATP-requiring pump linked to a proton gradient
- Release triggered by depolarization → Ca2+ influx through voltage-gated channels → vesicle fusion → exocytosis into synaptic cleft
- Action terminated by: reuptake into presynaptic terminal, uptake into glial cells, diffusion, or enzymatic inactivation
I. Catecholamines: Dopamine, Norepinephrine, Epinephrine
All three are synthesized from a common pathway starting from L-tyrosine.
Biosynthesis Pathway
| Step | Reaction | Enzyme | Cofactors | Notes |
|---|---|---|---|---|
| 1 (rate-limiting) | Tyrosine → L-DOPA | Tyrosine hydroxylase (TH gene) | BH4 (tetrahydrobiopterin) | Hydroxylates the ring; BH4 → BH2 |
| 2 | L-DOPA → Dopamine | DOPA decarboxylase | PLP (pyridoxal phosphate, B6) | Dopaminergic neurons stop here |
| 3 | Dopamine → Norepinephrine | Dopamine β-hydroxylase (DBH) | O2, Vitamin C (ascorbic acid) as electron donor, Cu2+ | Reaction occurs inside storage vesicles |
| 4 | Norepinephrine → Epinephrine | Phenylethanolamine N-methyltransferase (PNMT) | SAM (methyl donor) → SAH | Mainly adrenal medulla; some neurons |
Tyrosine itself comes from diet or from phenylalanine via phenylalanine hydroxylase (also BH4-dependent). Defect in PAH → PKU.
Degradation of Catecholamines
Two key enzymes act in any order, producing multiple metabolites:
| Enzyme | Location | Action | Specificity |
|---|---|---|---|
| MAO (Monoamine oxidase) | Outer mitochondrial membrane | Oxidizes carbon bearing amino group → aldehyde + NH4+ | MAO-A: NE + serotonin; MAO-B: broad phenylethylamines |
| COMT (Catechol-O-methyltransferase) | Many cells, erythrocytes | Transfers methyl group from SAM to catechol -OH | Broad catechols; requires B12 and folate indirectly |
- Final product of norepinephrine/epinephrine degradation: VMA (vanillylmandelic acid = 3-methoxy-4-hydroxymandelic acid) - excreted in urine; elevated in pheochromocytoma
- Dopamine degradation marker: HVA (homovanillic acid) in CSF - decreased in Parkinson's disease
- MAO in liver protects against dietary tyramine (found in aged cheese, red wine)
MAO Inhibitors (MAOIs) - clinical relevance:
- Irreversible (1st gen): iproniazid - antidepressant but causes "cheese effect" (tyramine → hypertensive crisis)
- Selective irreversible: clorgyline (MAO-A, antidepressant, still has cheese effect); deprenyl/selegiline (MAO-B, used in Parkinson's)
- Reversible (3rd gen): moclobemide (selective, reversible MAO-A inhibitor) - antidepressant without cheese effect
II. Serotonin (5-Hydroxytryptamine, 5-HT)
Synthesized from tryptophan, paralleling the catecholamine pathway.
| Step | Reaction | Enzyme | Cofactors |
|---|---|---|---|
| 1 | Tryptophan → 5-Hydroxytryptophan | Tryptophan hydroxylase | BH4 |
| 2 | 5-Hydroxytryptophan → Serotonin | DOPA decarboxylase (same enzyme as catecholamine pathway) | PLP |
- Degraded by MAO-A → 5-HIAA (5-hydroxyindoleacetic acid) excreted in urine; elevated in carcinoid syndrome
Melatonin from Serotonin
- Serotonin → N-acetyl serotonin (acetylation by Acetyl-CoA) → Melatonin (methylation by SAM via COMT-like reaction) in the pineal gland
- Responds to the light-dark cycle; organizes circadian and seasonal rhythms
III. Acetylcholine (ACh)
- Synthesized from choline + acetyl-CoA by choline acetyltransferase (ChAT) in the presynaptic terminal
- Degraded by acetylcholinesterase (AChE) in the synapse → choline + acetate
- Choline is recycled back to the presynaptic terminal via a high-affinity transporter
- Important for neuromuscular junction, autonomic ganglia, and CNS cognition (Alzheimer's disease: cholinergic deficit)
- AChE inhibitors (e.g., donepezil) used in Alzheimer's
IV. Glutamate and GABA
These are interconverted via the GABA shunt and are intimately linked to the TCA cycle.
| Feature | Glutamate | GABA |
|---|---|---|
| Type | Major excitatory NT in CNS | Major inhibitory NT in CNS |
| Synthesis | From α-ketoglutarate (TCA cycle) via transamination or from glutamine | Decarboxylation of glutamate by GAD (glutamic acid decarboxylase) |
| Cofactor | - | PLP (B6) |
| Termination | High-affinity uptake by neurons and glial cells | Uptake into glial cells (glial cells lack GAD - cannot synthesize GABA) |
| Clinical links | Excitotoxicity (stroke, ALS); NMDA receptors | Epilepsy, anxiety; benzodiazepines enhance GABA-A; valproate/tiagabine increase GABA |
The GABA Shunt
- In glial cells: GABA → glutamate (via GABA transaminase) → glutamine (via glutamine synthetase) → transported back to neurons
- In neurons: glutamine → glutamate → GABA (via GAD)
- This conserves glutamate and GABA in the CNS
- Tiagabine: inhibits GABA reuptake → adjunctive treatment for epilepsy
Vigabatrin irreversibly inhibits GABA transaminase → increases GABA levels → anticonvulsant
V. Glycine
- Major inhibitory NT in the spinal cord (and brainstem)
- Synthesized in neurons from serine by serine hydroxymethyltransferase (requires folate)
- Serine itself comes from 3-phosphoglycerate (glycolysis intermediate)
- Action terminated by high-affinity transporter reuptake
- Also acts as a co-agonist at NMDA glutamate receptors
VI. Aspartate
- Excitatory NT (functions in far fewer pathways than glutamate)
- Synthesized from oxaloacetate (TCA intermediate) via transamination
- Cannot cross the blood-brain barrier
VII. Nitric Oxide (NO)
- Synthesized from arginine + O2 by NO synthase (NOS) → citrulline + NO
- Cofactors: NADPH, FAD, FMN, BH4, calmodulin/Ca2+
- Atypical neurotransmitter - not stored in vesicles, not released by exocytosis (it is a gas)
- Acts by stimulating guanylate cyclase → increases cGMP → vasodilation, neurotransmission
- Also role in immune defense (kills tumor cells and parasites)
VIII. Histamine
- Synthesized from histidine by histidine decarboxylase (requires PLP)
- Present in mast cells and histaminergic neurons in the hypothalamus
- Degraded by MAO or histamine N-methyltransferase
Key Summary Table
| Neurotransmitter | Precursor | Key Enzyme | Cofactor | Type | Degradation |
|---|---|---|---|---|---|
| Dopamine | Tyrosine | Tyrosine hydroxylase (rate-limiting) + DOPA decarboxylase | BH4, PLP | Excitatory/modulatory | MAO, COMT → HVA |
| Norepinephrine | Dopamine | Dopamine β-hydroxylase | Vitamin C, Cu2+ | Excitatory | MAO, COMT → VMA |
| Epinephrine | Norepinephrine | PNMT | SAM | - | MAO, COMT → VMA |
| Serotonin | Tryptophan | Tryptophan hydroxylase | BH4, PLP | Modulatory | MAO-A → 5-HIAA |
| Melatonin | Serotonin | Acetyltransferase + COMT | Acetyl-CoA, SAM | - | - |
| GABA | Glutamate | GAD | PLP | Inhibitory (CNS) | GABA transaminase |
| Glycine | Serine | Ser hydroxymethyltransferase | Folate | Inhibitory (spinal cord) | Reuptake |
| Glutamate | α-KG (TCA) | Transamination | PLP | Excitatory | Reuptake |
| Acetylcholine | Choline + Acetyl-CoA | ChAT | - | Excitatory | AChE |
| Nitric oxide | Arginine | NOS | NADPH, BH4, Ca2+ | Gaseous/diffusible | Spontaneous (O2 radical) |
Clinical Correlates (High-Yield)
| Disease | Neurotransmitter Deficit/Excess | Mechanism |
|---|---|---|
| Parkinson's disease | ↓ Dopamine (nigrostriatal) | Loss of dopaminergic neurons; Tx: L-DOPA |
| Schizophrenia | ↑ Dopamine (mesolimbic) | Dopamine hypothesis; Tx: D2 blockers |
| Depression | ↓ Serotonin, ↓ NE, ↓ DA | Tx: SSRIs, SNRIs, MAOIs, TCAs |
| Alzheimer's disease | ↓ Acetylcholine | Loss of cholinergic neurons; Tx: AChE inhibitors |
| Epilepsy | ↓ GABA (or ↑ glutamate) | Tx: GABA enhancers (benzodiazepines, valproate) |
| Anxiety | ↓ GABA | Benzodiazepines ↑ GABA-A receptor sensitivity |
| Pheochromocytoma | ↑ VMA in urine | Excess catecholamine production from adrenal |
| Carcinoid syndrome | ↑ 5-HIAA in urine | Excess serotonin production |
| PKU | ↓ Dopamine, ↓ Serotonin | Phenylalanine blocks tyrosine and tryptophan transport to brain |
Source: Basic Medical Biochemistry - A Clinical Approach, 6e, Chapter 46 (CNS Biochemistry)
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