neuroscience 3 AI notes

Neurotransmitters and Their Receptors

Overview

• Importance of neurotransmitters in signaling within the nervous system.

• Receptors mediate the effects of neurotransmitters.

Categories of Neurotransmitters

Neuropeptides

• Comprised of 3-36 amino acids.

Small-Molecule Neurotransmitters

• Include biogenic amines, amino acids, purines, and indoleamines:

  • Biogenic Amines

    • Catecholamines: Dopamine, Norepinephrine, Epinephrine.

    • Indoleamine: Serotonin (5-HT)

    • Imidazoleamine: Histamine.

  • Amino Acids: Glutamate, Aspartate, GABA, Glycine.

  • Purines: ATP.

Peptide Neurotransmitters

• Over 100 peptides, usually 3-36 amino acids long, e.g., Methionine enkephalin.

Acetylcholine (ACh)

• First neurotransmitter identified.

• Involved in neuromuscular junctions, cardiac muscle synapses, and CNS.

• Synthesized from Acetyl CoA and Choline (via sodium-dependent transporter).

• Packaged into vesicles at a significant concentration (~10,000 ACh per vesicle).

Acetylcholinesterase (AChE)

• Hydrolyzes ACh into acetate and choline, allowing recycling.

• AChE breakdown rate: 5,000 molecules per second.

• Organophosphates inhibit AChE, leading to ACh accumulation and potential neuromuscular paralysis.

Nicotinic Acetylcholine Receptor

• Ionotropic receptor allowing cations (Na, K, Ca) to enter.

• Comprised of 5 subunits (2α, 1β, 1δ, 1γ/ε) for muscle-type receptors.

• Neuronal AChR has 3α and 2β with a wider pore for multiple cation entry.

Muscarinic AChR

• Metabotropic receptors mediate ACh effects in the brain (5 subtypes).

• Highly expressed in the corpus striatum: opens K channels, exerting an inhibitory effect on dopamine.

• In hippocampus, they close K channels for excitatory effects.

Glutamate

• Essential for normal brain function; estimates suggest it’s involved in half of brain synapses.

• Excessive release during trauma can cause excitotoxic damage.

• Non-essential amino acid; does not cross the blood-brain barrier, primarily synthesized from glutamine.

Glutamate Cycle

• Involves uptake by the SAT2 transporter and vesicular glutamate transporter (VGLUT).

• Glutamine synthetase plays a role in maintaining glutamate levels.

Ionotropic Glutamate Receptors

• Subtypes: AMPA, NMDA, kainate (allow Na+ to enter, K+ to exit).

• Produce excitatory postsynaptic responses.

• Commonly co-exist at excitatory synapses.

AMPA Receptors

• Composed of 4 subunits; pore opens upon glutamate binding.

NMDA Receptors

• Allows Ca2+ entry, acting as a second messenger.

• Requires glutamate, membrane depolarization, and glycine as co-agonist.

NMDA Receptor Structure

• Composed of 4 subunits; typically 2 glutamate and 2 glycine subunit combinations.

• Unique binding sites for calcium confer permeability to this ion.

GABA (Gamma-Aminobutyric Acid)

• Key neurotransmitter for inhibitory synapses in the CNS; occurs in 1/3 of brain synapses.

• Synthesized from glucose, pyruvate, or glutamine using Vitamin B6 as a cofactor.

• Packaged into vesicles by VIAAT.

GABA Removal

• Transported back into cells via GABA transporters (GATs).

• Primarily converted to succinate; other degradation pathways can lead to γ-hydroxybutyrate, a known substance of abuse.

GABA Receptors

• Types: GABAA (ionotropic) and GABAB (metabotropic).

• GABAA acts as chloride channels, while GABAB opens K+ channels and blocks Ca2+ channels.

Glycine

• Serves in half of the inhibitory synapses in the spinal cord; synthesized from serine.

• Similar to GABA in transport and removal mechanisms.

Glycine Receptors

• Comprise 5 subunits; ligand-gated chloride channels.

• Blocked by strychnine, affecting Cl- ionflow.

Biogenic Amines

• Active in CNS and PNS; implicated in various disorders.

• Derived from tyrosine; synthesized, released, and catabolized by various mechanisms.

Dopamine

• Primarily in the corpus striatum; associated with movement coordination and reward mechanisms.

Dopamine Synthesis

• Tyrosine converted via two enzymatic steps; loaded into vesicles by VMAT; reuptake by DAT.

• Degraded by MAO and COMT.

Dopamine Receptors

• All metabotropic; influence cAMP activation/inhibition.

Norepinephrine

• Functions primarily in locus coeruleus and sympathetic nervous system; influences arousal and attention.

Norepinephrine Synthesis

• Similar vesicular loading and degradation mechanisms as dopamine.

Norepinephrine Receptors

• α and β adrenergic receptors, both metabotropic with varying effects on neuronal excitability.

Epinephrine (Adrenaline)

• Present in lower concentrations than norepinephrine and dopamine; involved in regulating respiration.

Histamine

• Predominantly found in the hypothalamus involved in arousal and blood flow regulation.

Histamine Receptors

• Four types; antagonists can serve therapeutic purposes, including preventing motion sickness.

Serotonin (5-Hydroxytryptamine)

• Found in raphe nuclei; regulates sleep, wakefulness, and mood.

Serotonin Regulation

• Synthesized from tryptophan; SERT transports back, with degradation by MAO.

Metabotropic Serotonin Receptors

• Involved in emotional states, motor behaviors, and circadian rhythms.

• LSD impacts signaling, leading to hallucinations.

5-HT3 Receptors

• Ligand-gated ion channels targeted by therapeutic drugs for nausea prevention.

ATP/Adenosine

• ATP serves as a co-released neurotransmitter with various functions throughout the nervous system.

ATP/Adenosine Receptors

• Two types: P2X (ionotropic) and P2Y (metabotropic). Caffeine blocks adenosine receptors, contributing to stimulant effects.

Peptide Neurotransmitters

• Generated from pre-propeptides, processed into functional neuropeptides in vesicles.

Opioid Peptides

• Include endorphins, enkephalins, dynorphins; involved in various physiological processes and modulating behaviors.