Neurotransmitters

There are over 50 neurotransmitters.

Most common and clinically relevant are 6:

• dopamine
• acetylcholine
• norepinephrine and epinephrine
• histamine
• serotonin
• gamma-aminobutyric acid (GABA)

Mechanism of neurotransmitters

Neurotransmitter binds to receptors and activates enzymatic process in the effector tissue by directly opening ion channels or activation of a secondary messenger system.

1. Receptors coupled to ion channels

Include:

• Cholinergic nicotinic receptors
• GABA receptors

Binding of the neurotransmitter

   -> Opening of ion channels

   -> Changes in membrane potential
           OR

   -> Changes ionic concentration

2. Receptors coupled to adenyl cyclase

Include:

• beta-adrenergic receptors
• alpha-2

Binding of the neurotransmitter

   -> activation of adenyl cyclase

   -> catalyze ATP ---> cAMP

   -> cAMP leads to protein phosphorylation

   -> intracellular effect

3. Receptors coupled with diacylglycerol and inositol triphosphate

Include:

• alpha-1
• Cholinergic muscarinic receptors

Binding of the neurotransmitter

   -> release of diacylglycerol and inositol triphosphate

   -> protein phosphorylation

          and increased intracellular [Ca2+]

   -> intracellular effect

Neurotransmitters in autonomic nervous system

Two main neurotransmitter for ANS: acetylcholine (ACh) and norepinephrine

Autonomic neurons that secretes acetylcholine

   -> cholinergic

Autonomic neurons that secretes norepinephrine or epinephrine

   -> adrenerigc

Cholinergic receptors are of two types:

• muscarinic
• nicotinic

All ANS preganglionic neurons (sympathetic and parasympathetic)

   -> cholinergic (synapse with nicotinic receptors)

All postganglionic parasympathetic neurons

   -> cholinergic (synapse with muscarinic receptors)

All postganglionic sympathetic neurons

   -> adrenergic

Exception:

Postganglionic sympathetic neurons in sweat glands, piloerector muscles, and some blood vessels are cholinergic (synapsing with muscarinic receptors).

Neuromuscular junction (somatic nervous system)

   * neurotransmitter - acetylcholine

   * receptor - nicotinic

Synthesis and life cycle

Acetylcholine and norepinephrine - both synthesized in the terminal nerve ending.

Acetylcholine cycle

Synthesis - combination of acetyl-CoA with choline (in terminal nerve ending)

Storage - stored in vesicles (where it is protected from degradation)

Release - into the synaptic cleft

Binding - postsynaptic receptor activated when bound

Degradation - hydrolysed by cholinerase in the synaptic cleft

Recycle - choline (not acetylcholine) is taken up by neuron

Norepinephrine cycle

Synthesis - tyrosine -> DOPA -> dopamine

Storage - stored in vesicles (dopamine -> norepinephrine)

   -> In adrenal medulla, 80% of norepinephrine is converted into epinephrine

Release - Influx of calcium causes vesicles to fuse with membrane

Binding - postsynaptic receptor activated when bound

Removal - Norepinephrine is rapidly taken up into neuron

Metabolism - excess norepinephrine is

   -> methylated by catechol-O-methyltransferase (COMT) in the cleft, OR

   -> oxidised by monoamine oxidase (MAO) in neuronal mitochondria

   -> inactive products are excreted in urine as:

          * vanillylmandelic acid (VMA)

          * metanephrine

          * normetanephrine