Neurotransmitters: Types and Functions

• Neurotransmitters detailed lecture notes

Lecture Structure

• The lecture covers the definition of a neurotransmitter, its effects on neuronal activity, and an overview of different types.
• It also includes major classical neurotransmitters like amino acids and monoamines, along with a brief look at peripheral neurotransmitters.

Guide to Revision

• The lecture is short but packed with information.
• Chemical structures are primarily for illustrative purposes
• Diagrams contain sufficient detail with further info in the slide text

Defining Neurotransmitters

• Classical neurotransmitters are released from the presynaptic terminal
• Synthesized in the presynaptic cell
• Stored in presynaptic vesicles
• Released via vesicle exocytosis following an action potential.
• They activate postsynaptic receptors to transmit signals.
• Non-classical neurotransmitters aren't always stored/released by vesicles, or released presynaptically, but their release is regulated.

Considerations for Understanding Neurotransmitters

• Key considerations include identifying neurotransmitters in the body
• Knowing their actions at molecular, cellular, organ, and organism levels
• Understanding their synthesis, clearance from the synaptic cleft, and catabolism.

Key Neurotransmitters

• Neurons typically release only one type of neurotransmitter.
• Major neurotransmitters include glutamate, GABA, glycine (amino acid NTs), noradrenaline, 5-HT, dopamine, histamine (monoamine NTs), and acetylcholine.
• Classical neurotransmission involves the release of these neurotransmitters via presynaptic exocytotic vesicle release.

Beyond the Basics

• Neurons can release additional neurotransmitters alongside their primary one.
• Some can be released in classical, unconventional ways or either (adenosine),
• Other neurotransmitters: purines (like adenosine, ATP, ADP, AMP), gases (e.g., nitric oxide, carbon monoxide), neuropeptides (e.g., enkephalin, orexin), and lipids (e.g., endocannabinoids).

CNS Signal Integration

• Glutamate and GABA are the main drivers of neuronal activity through ionotropic receptors
• Glutamate causes depolarization, while GABA causes hyperpolarization.
• Other neurotransmitters modulate cell activity via receptors or ion channel activity.
• Acetylcholine (ACh) is the primary excitatory neurotransmitter in the peripheral nervous system (PNS).

Amino Acid Neurotransmitters

• The main three are Glycine, Glutamic acid and GABA

Glutamate

• Glutamate (Glu) is the primary excitatory neurotransmitter in the central nervous system (CNS).
• Glutamate is heavily associated with central cell metabolism, Krebs cycle and nitrogen metabolism
• Synthesis involves glutamate synthesis and its breakdown into glutamine.
• Removal occurs via reuptake into cells and astrocytes.

Hepatic Encephalopathy

• It involves glutamate and glutamine metabolism
• Liver failure elevates ammonium
• Increasing glutamine leading to astrocyte swelling
• Increased extracellular glutamate results in neuronal dysfunction

Glutamate Receptors

• Ionotropic include AMPA, Kainate, NMDA (non-NMDA)
• Metabotropic receptors mGluR1-8 have more limited medical uses.

Non-NMDA Glutamate Receptors

• AMPARs are the primary glutamate receptor for membrane depolarization
• Permeable mostly to Na+ and K+
• Kainate receptors are similar to AMPARs, but less common
• There are few therapeutically relevant drugs.

NMDA Glutamate Receptors

• NMDA glutamate receptors require a co-agonist (glycine or D-serine).
• Ligand- and voltage-gated
• Blocked by Mg2+ at rest, which is removed by cell depolarization.
• Permeable to Na+, K+, and Ca2+
• Play a key role in intracellular signalling
• There are drugs such as anaesthetics that can be used

GABA

• GABA is the main inhibitory neurotransmitter in the brain.
• GABA is synthesized from glutamate by glutamate decarboxylase (GAD).
• Removal happens at the synapse
• It is broken down to glutamate by GABA transaminase (GABA-T).

GABAA Receptors

• GABAA receptors are inhibitory anion channels.
• Chloride (Cl-) influx leads to hyperpolarization.
• GABAC / GABA-rho receptors are only found in the retina.
• Have high use as a drug target
• Useful for sedatives analgesics, muscle relaxants (central), and alcohol

GABAB Receptors

• GABAB receptors are Gio-linked GPCRs found throughout the CNS.
• GABAb receptors are targets for muscle relaxation

Glycine

• Glycine is easily obtained from main cell metabolism
• Glycine is the main inhibitory neurotransmitter replacing GABA in the spine
• Functions in motor control and pain sensitivity
• Glycine receptors are similar to GABAA receptors in structure and function with lonotrpic chloride channels
• There is a low drug relevance

Monoamine Neurotransmitters

• Monoamine NTs are categorized into catecholamines, indoles, and imidazoles.
• Catecholamines include dopamine, noradrenaline (adrenaline),
• Indoles include 5-hydroxytryptamine (melatonin)
• Imidazoles include Histamine

Dopamine

• Dopamine is synthesized from tyrosine
• The key step L-DOPA to dopamine is mediated by DOPA decarboxylase (DOPA-D).
• Dopamine is removed by the dopamine reuptake transporter (DAT)
• Dopamine catabolism happens with the aid of monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), and catechol-O-methyltransferase (COMT)
• Some extracellular catabolism is by MAO-B.

Dopaminergic Nuclei

• Dopaminergic nuclei include the substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and arcuate nucleus of the hypothalamus

Dopaminergic Functions

• Motor control (e.g., Parkinson's disease, Huntington's disease) occurs via the nigrostriatal pathway.
• Reward and pleasure occur through the Mesolimbic pathway.
• Cognition, attention and memory happens via mesocortical pathway
• Hormonal regulation happens via Tuberoinfundibular pathway

Dopamine Receptors

• All dopamine receptors are GPCRs
• D1-like family: D1 & D5, Gs-linked receptors
• D2-like family: D2-4, Gio linked receptors.
• With high impact drugs generally D2 > D1 > D3-5
• Dopaminergic pharmacology is important for emesis, motor disorders (e.g. Parkinson's disease), psychosis, and drug addiction.

Noradrenaline

• Also known as norepinephrine, is synthesised from dopamine by dopamine beta-hydroxylase (DBH).
• Removed by noradrenaline reuptake transporter (NET).
• Catabolized by enzymes MAO-A and COMT.

Noradrenergic Pathways

• Noradrenaline neurons are located in the locus coeruleus.
• Possess widespread innervation in the brain
• Stimulant in the CNS, increasing arousal, alertness, reward, and excitement.
• Enhances the release of 5-HT and dopamine.
• CNS is a major drug target and contains antidepressants, anxiolytics etc.

Adrenoceptors

• Adrenoceptors are metabotropic
• They are either A1 – Gq linked, A2 - Gio linked and B1-3 - Gs linked.
• A1 and B1 are mostly common receptors in the CNS
• Agonists are often sedatives with antagonists helping treat depression

5-HT Serotonin

• Serotonin is metabolised from tryptophan.
• Removal is aided with serotonin reuptake transporter (SERT).
• Catabolism occurs by MAO-A.

Serotonergic Pathways

• There are dorsal raphe nuclei in the brainstem with complex, wide brain innervation.
• Its effect includes mood, anxierty, body temperature, sexual function and cerebral vasoconstriction

5-HT receptors - ionotropic

• 5-HT has a ionotropic cation channel (5-HT3 receptor)
• They posses a structured like nAChR and GABAA receptors
• Permeable to Na+ and K+
• Plays a role in brain vomiting and memory pathways

5-HT Receptors - Metabotropic

• Numerous types exist (5-HT1-2,4-7)
• Two types exist 5-HT1,5 which is Gio-linked and 5-HT2,4,6-7 which is Gs-linked
• Mostly common and in serotonergic pathways
• CNS aids in mood, pain, migraine and vomitting

Histamine

• Histamine is a result of histidine production
• There are receptors H₁ – Gq-linked, H2 - G5-linked, H3 & H4 where it is (Gio-linked)
• Plays a part in modest drug relevance
• Major role in the periphery to maintain non-neurotransmission signalling

Histaminergic Pathways

• Histaminergic pathways comes from cells in the tuberomammillary nucleus (TMN).
• It's action include sleep regulation and endocrine activity

Acetylcholine

• Acetylcholine is a major excitatory neurotransmitter
• It is synthesized from choline and acetyl co-A by choline acetyltransferase.
• It can be catabolized extracellularly by acetylcholinesterase.

Cholinergic Nuclei

• There have numerous subcortical and brainstem
• It generally increases stimulus

CNS Cholinergic Areas

• Three main areas Basal forebrain nuclei, the Mesopontine nuclei and in the Striatum.

Cholinoceptors

• Two key types include, iIonotropic for nicotinic receptors, metabotropic for muscarinic acetycholine receptors.

Purines

• Adenosine: varied classical non classical release mechanisms
• ATP/ADP/AMP: ATP packed with NA

Neuropeptides

• Many different neuropeptides, e.g. Enkephalin sleep regulation
• Produced from protein cleavage
• Released with vesicles
• Occur in the Gl tract

Endocannabinoids

• Have endogenous agonists
• They have significant receptors

Stimulants / depressants

• Stimulants increase CNS, arousal, alertness, energy
• Depressants decrease CNS, drowsiness, calmness

Peripheral Neurotransmitters

• Consists of autonomic nerves, enteric system and somatic

Summary

• Key neurotransmitters listed in lecture
• Their pathways and metbaolism
• General NTs