Neurotransmitters

Vocabulary:

• Neurotransmitter: A chemical present/synthesized within a presynaptic neuron, gets released during synaptic activity as a response to Ca2+, there are postsynaptic receptors that will bind it, it produces a consistent physiological response when it binds to its receptor, and has a mechanism for removal/inactivation. After release, will diffuse, undergo reuptake to glial transport followed by enzymatic processing via amino acids and biogenic amines, degradation in the cleft (for ACh, ATP, and neuropeptides), bind to an intracellular receptor, or spontaneously oxidize

  • ACh: Made from choline (in plasma) and acetyl CoA (from glucose), removed from a synapse by acetylcholinesterase (AChE). Main source is the basal forebrain. Use a lot in the parasympathetic division of the visceral motor system, along with all somatic motor neurons at NMJs). Organophosphates in some insecticides deactivate AChE. After breakdown, the choline is reused and the acetate diffuses away. Within the CNS, contributes to attention and memory

  • Glutamate: Excitatory, made from glutamine, removed by transporters. Glutamine comes from plasma, which is converted via glutaminase. Inactivation after the reuptake of Na+ via cotransport into presynaptic terminals and glia. In glia, it is converted back to glutamine and released to be taken up again by a neuron. Most common neurotransmitter, vital for normal brain functioning. Trauma resulting in excess glutamate can lead to excitotoxicity. The glutamate-glutamine cycle regulates the amount of glutamate in the synaptic cleft

  • Gamma-aminobutyric acid (GABA): Inhibitory, made from glutamate via glutamic acid decarboxylase (GAD) which limits production rate, removed by transporters like Na+ and Cl-. Can be reuptaken by neurons and glia, enzymatic breakdown allows product to enter the tricarboxylic acid cycle. Most common inhibitory neurotransmitter, about 1/3 of synapses response to in. Found in local circuit interneurons, and projections from the corpus striatum, cerebellar cortex purkinje cells, and scattered in the PNS. GABAA is ionotropic, GABAB is metabotropic

  • Glycine: Inhibitory, made from serine during glucose metabolism, removed by transporters. Can be uptaken to a neuron or glia. Found in about half of inhibitory synapses in the spinal cord, always ionotropic. NDMA receptor co-agonist

  • Catecholamines: Consist of epinephrine, norepinephrine, and dopamine. Made from tyrosine, with production rate limited by tyrosine hydroxylase. Removed by transporters, MAD, or COMT in ICF

  • Serotonin: Made from tryptophan, removed by transporters or MAO in ICF

  • Histamine: Made from histidine, removed by transporters

  • ATP: Made from ADP, removed via hydrolysis breakdown to AMP and adenosine

  • Neuropeptide: Start as prepropeptides → propeptides, undergo anterograde axonal transport and after the propeptide is cleaved enzymatically it is an active signaling molecule, will only bind to GPCRs, act as neuromodulators frequently, undergo enzymatic degradation in the synaptic cleft by proteases

    • Prepropeptides: Will become neuropeptides, synthesized in the cell soma and cleaved to propeptides. Formed from amino peptides (made by protein synthesis). “pre” part helps it find the ER, cleaved there

    • Propeptide: A cleaved prepropeptide as it enters the endoplasmic reticulum, packaged along enzymes into large dense-core vesicles in the Golgi body, cleaved into neuropeptides “pro” part helps find the golgi apparatus

  • Endocannabinoids: Bind to intracellular receptors and undergo degradation in the neuron. Inhibit inhibition, made by membrane lipids, don’t use vesicles

  • Nitric oxide: Spontaneously oxidizes to be removed, made from arginine, production rate limited by nitric oxide synthase

• Glutamic acid decarboxylase (GAD): Found almost exclusively in GABA-synthesizing neurons, coverts glutamate to GABA, requires pyroxidal phosphate (from vitamin B6) as a cofactor

• Gamma hydroxybutyrate: The “date rape” drug, induces euphoria, memory deficits, and unconsciousness. Inactivates GABA

• Hyperglycinemia: A genetic defect as a result of glycine irregularities, causes neonatal developmental delays, lethargy, and seizures

• Strychnine: A competitive antagonist (blocks binding site) for glycine receptors in rat poison, leads to muscular convulsions

• Myasthenia gravis: Autoimmune AChR destruction at NMJs, treated by blocking AChE

• Neuromodulator: Increases or decreases synaptic activity, doesn’t directly activate ion-channel receptors, and has more prolonged effects that neurotransmitters. Act on groups of cells and diffuse widely, targeting both electrical and chemical synapses. They can act on presynaptic or postsynaptic neurons to regulate synthesis/release of synaptic transmitters, alter RMP, modify receptors, or modulate intracellular signaling pathways. Same molecules can also be neurotransmitters sometimes. Does not cause an electrical signal

• Co-transmission: Release of neurotransmitters and neuromodulators at the same time, sometimes within the same vesicle

• Small-molecule neurotransmitter: Have rapid effects ionotropically, though biogenic amines are a type that are slower with metabotropic receptors and GPCRs. Made in presynaptic terminals, packaged in vesicles by vesicular transport. Made in presynaptic terminals

• Biogenic amine: Have slower effects than typical small molecule neurotransmitters, have ongoing effects, a subclass of small molecule neurotransmitters

• Enzyme: Synthesized within the soma, brought to a synapse via anterograde axonal transport and remain in the axon terminal

• H+ ATPase pumps: Pump protons into a vesicle during vesicular transport

• H+ exchanger: Swaps protons in the vesicle for neurotransmitters

• Vesicle: A membrane carrying something

  • Small diameter: Less than 50 nm, have a clear core

  • Large diameter: Have an electron-dense core

  • Sodium cotransport: Required in order to inactivate a neurotransmitter

• Ionotropic receptors: Usually have 5 subunits, specified to be synapse-specific based on combinations of subunits

• Metabotropic receptors: Have 1-2 subunits with 7 transmembrane domains, all GPCRs

• G protein-coupled receptor (GPCR): Metabotropic, contain an intracellular binding site for a g protein. Exchange GDP for GTP to dissociate the g protein. Subclasses based on function of primary subunit

  • Gi: Decreases cAMP synthesis

  • Gs: Increases cAMP synthesis, can activate PKA

  • Gq: Increases levels of calcium, can activate PKC

• G-protein: Binds to GPCRs, has alpha, beta, and gamma subunits. Released upon GDP → GTP, dissociating into alpha subunit and beta-gamma subunit to start signaling cascades

• Alpha-bungarotoxin: Blocks NMJ receptors

• Myasthenia gravis: An autoimmune disorder involving destruction of AChRs in NMJs, shows weakness with repetitive movements and is treated with AChE blocking drugs

Ionotropic neurotransmitter receptors and subunits:

• ACh

  • nACh: Excitatory and nonselective to cations and nicotine, activated when 2 ACh bind. Located at NMJs with skeletal muscles, ganglia of visceral motor system, and CNS. Memory and attention

    • alpha 1-10

    • beta 1-4

    • gamma

    • delta

    • epsilon

• Glutamate: Excitatory in vertebrates, permeable to Na+ and K+

  • AMPA: Produces large and fast/sharp currents

    • GluA1

    • GluA2

    • GluA3

    • GluA4

  • NMDA: Also permeable to Ca2+, require glycine as a co-agonist. Blocked by Mg2+ until a membrane is depolarized, typically due to nearby AMPAR. Function as coincidence detectors, requiring glutamate and depolarization

    • GluN1

    • GluN2A

    • GluN2B

    • GluN2C

    • GluN2D

    • GluN3A

    • GluN3B

  • Kainate: Produces shallow and long currents

    • GluK1

    • GluK2

    • GluK3

    • GluK4

    • GluK5

• GABA: Permeable to Cl-, reverse potential lower than AP threshold. Agonists include benzodiazepines, sleeping pills, ketamine, and ethanol. Barbituates potentiate signaling and are used for anesthesia and epilepsy treatment

  • Alpha 1-6

  • Beta 1-3

  • Gamma 1-3

  • Delta

  • Epsilon

  • Theta

  • Meu

  • Rho

• Glycine: Permeable to Cl-

  • Alpha 1-6

  • Beta

• Serotonin

  • 5-HT3A

  • 5-HT3B

  • 5-HT3C

  • 5-HT3D

  • 5-HT3E

• ATP

  • P2X1

  • P2X2

  • P2X3

  • P2X4

  • P2X5

  • P2X6

  • P2X7

Metabotropic neurotransmitter receptors and subunits:

• ACh

  • mACh: One protein with 7 transmembrane domains, can be inhibitory or excitatory. Has receptors in the CNS (like corpus striatum, vomiting center, and hippocampus) and PNS (like with the parasympathetic nervous system and sympathetic innervation of sweat glands). Agonistic to ACh and muscarine from poisonous mushrooms, antagonistic to atropine (for pupil dilation), scopolamine (to prevent motion sickness) and for asthma treatment

    • M1

    • M2

    • M3

    • M4

    • M5

• Glutamate: Heterodimers

  • Class I: Excitatory (normally)

    • mGlu1

    • mGlu5

  • Class II: Inhibitory (normally), in retina

    • mGlu2

    • mGlu3

  • Class III: Inhibitory (normally), in retina

    • mGlu4

    • mGlu6

    • mGlu7

    • MGlu8

• GABA: Inhibit adenylyl cyclase, cause the membrane potential to be more negative. Heterodimers, inhibitory

  • GABAB1

  • GABAB2

• Dopamine

  • D1: Excitatory

  • D2: Inhibitory

  • D3

  • D4

  • D5

• Adrenergic

  • Alpha

    • Alpha1A

    • Alpha1B

    • Alpha1D

    • Alpha2A

    • Alpha2B

    • Alpha2C

  • Beta

    • Beta1

    • Beta2

    • Beta3

• Histamine

  • H1

  • H2

  • H3

  • H4

• Serotonin

  • 5-HT1A

  • 5-HT1B

  • 5-HT1D

  • 5-HT1E

  • 5-HT1F

  • 5-HT2A

  • 5-HT2B

  • 5-HT2C

  • 5-HT4

  • 5-HT5A

  • 5-HT6

  • 5-HT7

• Purines

  • Adenosine

    • A1

    • A2A

    • A2B

    • A3

  • ADP/ATP

    • P2Y1

    • P2Y2

    • P2Y4

    • P2Y6

    • P2Y11

    • P2Y12

    • P2Y13

    • P2Y14