Chapter 6 Flashcards
What are the common requirements to be labeled a neurotransmitter?
- present in presynaptic neuron
- released during synaptic activity
- postsynaptic receptors
- mechanism for inactivation
- exogenous mechanism mimics endogenous release
- blocked by antagonists
What is the general distinction between neurotransmitters and neuromodulators?
Based on effects of the molecule. Neuromodulators don’t directly cause electrical signals.
How do neuromodulators function?
They modulate synaptic transmission by altering neurotransmitter synthesis/release, modifying receptors or intracellular signaling paths, and modifying resting membrane potential.
What is the signaling speed of neuromodulators compared to neurotransmitters?
Neuromodulators generally have slower, more diffuse signaling.
What are the categories of neurotransmitters?
Small molecules (monoamines), neuropeptides, and nontraditional (unconventional) neuromodulators.
Where are small molecule neurotransmitters produced? How fast is the signaling?
Synthesized at the axon terminal, they provide faster signaling than neuropeptides.
What are examples of small molecule neurotransmitters?
ACh, amino acids, biogenic amines/monoamines, and purines.
How are neuropeptides synthesized?
They are synthesized in the cell body and transported anterogradely.
What are examples of unconventional neuromodulators?
Endocannabinoids and nitric oxide.
What are ionotropic receptors?
They provide faster signaling and are less selective than voltage-gated channels.
What is the structure of ionotropic receptors?
Composed of 3-5 subunits, grouped into classes based on common structures and pharmacological responses.
What are metabotropic receptors?
G-protein coupled receptors that initiate intracellular signaling cascades; slower response
What are the functional classifications of metabotropic receptors?
Gs, Gi, Gq
Gs activates adenylyl cyclase, Gi inhibits adenylate cyclase, and Gq activates phospholipase C.
What is acetylcholine (ACh)?
And where is it produced?
A neurotransmitter synthesized in specific neuron cell bodies.
What condition is associated with ACh?
Myasthenia gravis
Autoimmune disorder in which antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles
What special characteristics does NMDA have?
Magnesium block and glycine co-agonist.
What are the receptor types for GABA?
GABA-A receptors with specific permeability.
Where is dopamine released from?
Substantia Niagra pars compacta (SN) and Ventral tegmental area
Both midbrain regions
Where is the cell body distribution for norepinephrine?
Locus Coeruleus
What are the basic signaling paths for adrenergic receptors?
a1, a2, B1, and B2
- Alpha-1 increases intracellular calcium
- Alpha-2 inhibits adenylate cyclase
- Beta-1/Beta-2 activate adenylte cyclase
What is the receptor affinity for norepinephrine and epinephrine?
Alpha-1 has greater affinity for norepinephrine than epinephrine.
Where are serotonin-synthesizing/distributing neurons located?
Raphe nuclei
Where are histamine-synthesizing neurons located?
Tuberomammillary nucleus of hypothalamus
What role does ATP play in neurotransmission?
All secretory vesicles contain ATP, but it is not always a neurotransmitter/neuromodulator.
What are the types of adenosine receptors?
A1, A2x, and A3 (non-neuronal)
All G protein receptors
How are neuropeptides synthesized?
prepropeptide -> endoplasmic reticulum -> propeptide + enzymes -> golgi apparatus -> vesicles -> anterograde axoplasmic transport
This is all in the soma
What is the mechanism of action for endocannabinoids?
They inhibit GABA release from presynaptic cells.
What is nitric oxide’s role in neurotransmission?
It diffuses out of the cell and activates soluble guanylyl cyclase (GTP) in the cytoplasm.
What are the hypothesized functions of nitric oxide in the nervous system?
Plasticity and neurodegenerative diseases.
What blocks nicotinic receptors at the neuromuscular junction?
alpha bungarotoxin
However, this will not block postganglionic neurons
How is ACh synthesized?
- Acetyl CoA from glucose
- choline from plasma
- choline acetyltransferase (ChAT)
Where is a major source of ACh?
basal forebrain
What deactivates acetylcholinesterase (AChE)?
organophosphates
Such as sarin and insectisides
Ionotropic effects of ACh
- excitatory: Na+ and K+
- neuromuscular junction at skeletal muscle
- ganglia of visceral motor system
- CNS
Metabotropic effects of ACh?
- parasympathetic postganglionic neurons
- CNS
What is the ionotropic ACh receptor? What is unique about it?
Nicotinic receptors (nAChR); requires 2 ACh molecules to activate
Muscarinic receptors (mAChR)
- ACh agonist
- from poisonous mushroom
Atropine
ACh antagonist; pupil dilation
Scopolamine
ACh antagonist; prevents motion sickness
Ipratropium
ACh antagonist; asthma treatment
How is glutamate synthesized?
glutamine taken up from plasma and converted in the mitochondria by glutaminase
What deactivates glutamate?
- reuptake in the presynaptic terminal
- glia (glutamine synthesis converts back to glutamine)
Ionotropic effects of glutamate
excitatory in vertebrates
Metabotropic effects of glutamate
excitatory or inhibitory
GluR 1 is excitatory, 2 and 3 inhibitory
What are the ionotropic glutamate receptors?
AMPA, NMDA, and Kainate
all agonists
What are AMPA, NMDA, and Kainate permeable to?
Na+ and K+
NMDA also permeable to Ca2+
What are the different current patterns of glutamate ionotropic receptors?
Hint: Think of graphs
- AMPA: sharp, fast
- NMDA: slower
- Kainate: slower inward current and longer to die out
How are NMDA receptors unique?
- involves Mg2+ blocking the pore until it is depolarized
- glycine co-agonist
How are Kainate receptors unique?
Autoreceptors
Effect of glutamate metabotropic receptors (mGluR) in CNS and PNS?
CNS: cognitive processes
PNS: vision
How is GABA synthesized?
glucose to glutamate during the TCA, and then glutamic acid to GABA via glutamic acid decarboxylase (GAD)
GAD requires cofactor vitamin B6
How is GABA inactivated?
- reuptake neurons and glia by GAT
- enzymatic breakdown into succinate and Y hydroxybutyrate
hydroxybutyrate is the date rape drug
Are projection neurons mainly excitatory or inhibitory?
Excitatory
What is the ionotropic GABA A receptor permeable to?
Cl-
Benzodiazepine
GABA agonist; calming effect
Zolpidem
GABA agonist; sedative that treats insomnia
Ketamine
GABA agonist; anesthetic and treats depression
Alcohol (ethanol)
GABA agonist; depressant
What do barbituates do?
enhance GABA signaling; anesthesia and epilepsy
Function of metabotropic GABA B receptors
- inhibits adenylyl cyclase
- activates inward K+ current
- blocks Ca2+ channels
How is glycine synthesized?
serine precursor; serine hydroxylase methyltransferase
How is glycine inactivated?
Glycine specific Na+ cotransporter
by recycling
Is glycine inhibitory or excitatory? Where are these synapses?
inhibitory; spinal cord
What ion are ionotropic glycine receptors permeable to?
Cl-
Strychnine
Glycine competitive antagonist
What is GABA?
GABA (Gamma-Aminobutyric Acid) is a neurotransmitter that inhibits neuronal activity.
What are the receptor types for GABA?
GABA-A (ionotropic, ligand-gated Cl⁻ channels).
What is the permeability of GABA-A receptors?
Allows Cl⁻ ions to flow into the cell, causing hyperpolarization.
How is GABA synthesized?
Synthesized from glutamate by the enzyme GAD (glutamate decarboxylase).
How is GABA reuptaken?
Reuptake via GABA transporters (GAT).
How is GABA degraded?
Degraded by GABA transaminase to succinic semialdehyde, which is further metabolized.
Where is dopamine synthesized?
Synthesis Location: Substantia nigra, ventral tegmental area (VTA).
What are the projection areas for dopamine?
Caudate, putamen, prefrontal cortex, nucleus accumbens.
What are the receptor types for dopamine?
D1, D2, D3, D4, D5 (all are GPCRs).
How is dopamine synthesized?
Synthesized from tyrosine via tyrosine hydroxylase → L-DOPA → dopamine.
How is dopamine reuptaken?
Reuptake by dopamine transporters (DAT).
How is dopamine degraded?
Degraded by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
Where is norepinephrine synthesized?
Synthesis Location: Locus coeruleus (LC).
What are the projection areas for norepinephrine?
Cortex, hippocampus, spinal cord.
What are the receptor types for norepinephrine?
Alpha-1, Alpha-2, Beta-1, Beta-2 (all GPCRs).
How is norepinephrine synthesized?
Synthesized from dopamine via dopamine beta-hydroxylase.
How is norepinephrine reuptaken?
Reuptake by norepinephrine transporters (NET).
How is norepinephrine degraded?
Degraded by MAO and COMT.
Where is epinephrine synthesized/distributed from?
Medullary epinephrine neurons
What is the role of epinephrine?
Fight-or-flight response.
What are the receptor types for epinephrine?
Alpha-1, Alpha-2, Beta-1, Beta-2 (all GPCRs).
How is epinephrine synthesized?
Synthesized from norepinephrine by the enzyme phenylethanolamine-N-methyltransferase (PNMT).
How is epinephrine reuptaken?
Reuptake by norepinephrine transporters (NET), although less prominent than in norepinephrine.
How is epinephrine degraded?
Degraded by MAO and COMT.
What is the role of ATP in neurotransmission?
Present in all synaptic vesicles but is not always the primary neurotransmitter. It acts as a neuromodulator through P2X receptors (ionotropic).
How is ATP synthesized?
Synthesized in the mitochondria from ADP or AMP.
How is ATP reuptaken?
Reuptake by P2Y and P2X receptors.
How is ATP degraded?
Degraded by ectonucleotidases to adenosine.
What are P2X receptors?
Ionotropic receptors activated by ATP.
What is the function of P2X receptors?
Allow cation influx (Na⁺, Ca²⁺), which causes depolarization.
How is ATP reuptaken via P2X receptors?
ATP is cleaved into ADP and AMP by ectonucleotidases.
How are ADP and AMP degraded?
ADP and AMP can be further broken down to adenosine, which is removed via nucleoside transporters.
What are the receptor types for adenosine?
A1, A2A, A2B, A3 (all GPCRs).
How is adenosine synthesized?
Derived from ATP through ectonucleotidase activity (hydrolysis of ATP to adenosine).
How is adenosine reuptaken?
Reuptake via equilibrative nucleoside transporters (ENTs).
How is adenosine degraded?
Degraded by adenosine deaminase (ADA) to inosine.
How are neuropeptides synthesized?
Synthesized as larger precursor proteins that are cleaved into active peptides (e.g., pro-opiomelanocortin → ACTH, beta-endorphins).
What are the receptor types for neuropeptides?
Always metabotropic receptors (GPCRs).
How is neuropeptide reuptake characterized?
Typically, reuptake is not significant. Neuropeptides are often degraded locally.
How are neuropeptides degraded?
Degraded by peptidases and other proteolytic enzymes.
What are the major types of endocannabinoids?
Anandamide, 2-AG (2-arachidonoylglycerol).
How are endocannabinoids synthesized?
Synthesized on demand from membrane lipids (e.g., phospholipids) in response to Ca²⁺.
What are the receptor types for endocannabinoids?
CB1 (central nervous system), CB2 (peripheral immune system) - both GPCRs.
What is the mechanism of endocannabinoids?
Retrograde signaling; they inhibit presynaptic neurotransmitter release (e.g., GABA, glutamate).
How is anandamide reuptaken?
Anandamide is reuptaken via fatty acid amide hydrolase (FAAH).
How are endocannabinoids degraded?
Degraded by FAAH (for anandamide) and monoacylglycerol lipase (MAGL) (for 2-AG).
How is nitric oxide synthesized?
Synthesized from L-arginine by nitric oxide synthase (NOS), activated by Ca²⁺-calmodulin.
What is the mechanism of nitric oxide?
Diffuses out of the cell, activates soluble guanylyl cyclase (SGC) in the cytoplasm, producing cGMP.
How is nitric oxide reuptaken?
No reuptake since NO is a gas and diffuses freely.
How is nitric oxide degraded?
Spontaneous oxidation, inactivation via reactive nitrogen species.
What are the types of adrenergic receptors?
- Alpha-1: Increases intracellular calcium.
- Alpha-2: inhibits adenylate cyclase
- Beta-1/Beta-2: activate adenylate cyclase
Where are norepinephrine and epinephrine synthesized?
Norepinephrine is synthesized in the locus coeruleus and epinephrine in the adrenal medulla.
How are norepinephrine and epinephrine reuptaken?
Both norepinephrine and epinephrine are primarily recycled via the norepinephrine transporter (NET).
How are norepinephrine and epinephrine degraded?
MAO and COMT are responsible for the breakdown.
What does the neuropeptide Substance P do?
pain and temperature perception
What does the neuropeptide Y do?
feeding behavior
What does D-1 type dopamine receptor do?
Acivate adenylate cyclase (Gs)
What does D-2 type dopamine receptor do?
Inactivate adenylate cyclase (Gi)
What is a function of dopamine?
Stimulates vomiting
Is Parkinson’s associated with a loss or increase of dopamine?
Loss
What can lead to cataplexy (sudden muscle weakness)?
Hint: related to dopamine
Dopamine agonists
Propanolol
B receptor antagonist (norepinephrine and epinephrine) used for migranes
