Neurotransmitters

Neurotransmitters are released from the presynaptic cell on stimulation and bind to receptors to mediate their effects.

The synapse is a connection between a neuron and its target cell (which is not necessarily a neuron). The presynaptic element is the synaptic end bulb of the axon where Ca2+ enters the bulb to cause vesicle fusion and neurotransmitter release. The neurotransmitter diffuses across the synaptic cleft to bind to its receptor. The neurotransmitter is cleared from the synapse either by enzymatic degradation, neuronal reuptake, or glial reuptake.

Following are the important neurotransmitters:

1. Acetylcholine: It is synthesized from choline and acetyl CoA by the enzyme choline acetyltransferase. The enzyme acetyl-cholinesterase breaks down ACh to choline and acetate thus terminating action of ACh. Most of the choline is then recycled to form more ACh. Ach binds to Nicotinic and muscarinic receptors. Nicotinic acetylcholine receptors are transmitter gated ion channels permeable to Na, K and Ca ions. Muscarinic acetylcholine receptors are G protein linked receptors. ACh is a neurotransmitter at the neuromuscular junction and preganglionic sympathetic and parasympathetic neurons including the adrenal medulla. It is also released by postganglionic parasympathetic neurons and postganglionic sympathetic neurons innervating the eccrine sweat glands and blood vessels in skeletal muscles (causes dilation). In the CNS, ACh acts on the somatic and visceral motor nuclei in the brainstem, basal nucleus of Meynert (degenerates in Alzheimer’s) and striatum (degenerates in Huntington’s Disease).

2. Biogenic amines - Norepinephrine, epinephrine and dopamine: All three biogenic amines are derived from amino acid tyrosine. Tyrosine hydroxylase converts tyrosine to L-dopa. L-dopa is converted to dopamine by dopa decarboxylase. Dopamine can be converted to NE by enzyme dopamine beta hydroxylase. NE is methylated to epinephrine by phenylethanolamine-N methyltransferase (PNMT). The enzymes COMT and MAO convert biogenic amines to inactive metabolites. COMT is catechol-O-methyltransferase. It is present in tissues but not in nerve endings. MAO is monoamine oxidase and is present in presynaptic nerve terminals. Metanephrine, normetanephrine, MOPEG/phenyl glycols and vanillylmandelic acid or 3-methoxy-4-hydroxy-mandelic acid are the breakdown products of epinephrine and NE.

   Epinephrine acts via GPCR. It is the major hormone produced by the adrenal medulla.

   NE also acts via GPCR. NE is the neurotransmitter of postganglionic sympathetic neurons and locus coeruleus in the midbrain and pons. Role in anxiety (↑), depression(↓), panic attacks and mania.

Dopamine is a neurotransmitter in arcuate nucleus of the hypothalamus, ventral tegmental area, kidneys, retina, olfactory bulb, periaqueductal grey matter and substantia nigra. In the kidneys it produces renal vasodilation, diuresis and natriuresis. There are 5 types of dopamine receptors, D1-5. All are GPCR. D1 receptors have been associated with cognition, working memory and attention. Activation of D1 receptors may lead to opening of sodium channels causing depolarisation or opening of potassium channels causing inhibition. D1 causes rise in cAMP levels while D2 causes fall in cAMP level. D2 receptors are inhibitory and regulate mood, emotional stability and movement control (in the basal ganglia). D5 receptors are mainly associated with pain signals. D3 and D4 receptors are located mainly in the limbic system. Dopamine levels are decreased in Parkinson’s disease, depression, ADHD and increased in schizophrenia and mania. Most drugs of addiction increase dopamine in the striatum (reward behavior).

3. Serotonin: It is produced from tryptophan and degraded by enzyme MAO to 5 hydroxyindoleacetic acid or 5-HIAA. It is converted to melatonin in the pineal gland. Apart from CNS, serotonin is present in the enterochromaffin cells of the GI mucosa and neurons in the enteric nervous system. After secretion, it is removed from the interstitial space by the serotonin-selective reuptake transporter (SERT) which is expressed in the epithelial cells. It has multiple receptors which are typed as 5HT 1-7, there are subtypes of these as follows:

5-HT plays a role in many GI functions and in sending signals from the gut to the CNS. Actions of serotonin released from mucosal enterochromaffin cells include activation of intrinsic reflexes such as peristalsis, segmentation, secretion and vasodilation. Serotonin can also activate signals sent to the CNS that stimulate digestive reflexes and can cause abdominal pain and discomfort, satiety, or nausea. Serotonin can lead to local inflammation and promote neural regeneration and survival of the interstitial cell of Cajal.

Many tissues express 5-HT receptors, and actions of 5-HT outside of the gut include vasoconstriction or vasodilation (depending on the vascular bed), platelet aggregation (5HT2A receptor), hematopoiesis, regulation of bone density, bronchoconstriction, itching sensation and nociception. Furthermore, 5-HT appears to be involved in heart and mammary development, as well as oocyte maturation.

4. GABA: Gamma amino butyric acid or GABA is produced from glutamic acid by the action of enzyme glutamic acid decarboxylase. It is an inhibitory neurotransmitter in the CNS. It has GABA A and B receptors. GABA A is a transmitter gated ion channel permeable to Cl ions. GABA A is the site of action of benzodiazepines and barbiturates. GABA B is a GPCR linked to K channel. In Huntington’s disease, GABA is deficient leading to choreiform movements. Tetanospasmin inhibits the release of GABA and glycine leading to spasms, rigidity, trismus etc.

5. Glycine: It is a major inhibitory neurotransmitter in the spinal cord and brainstem. Glycine receptor is a transmitter gated Cl channel. Tetanospasmin inhibits the release of GABA and glycine leading to spasms, rigidity, trismus etc.

6. Glutamate: It is the major excitatory neurotransmitter in the CNS. It binds to N methyl D aspartate or NMDA receptors and kainate or quisqualate receptors which are transmitter gated ion channels permeable to Na, K and Ca ions. Some glutamate receptors are GPCR.