5.1 NT Systems Flashcards
How are monoamines synthesized?
created by modifying certain AAs
Catecholamines (DA–> NE–> E) from tyrosine (via tyrosine hydroxylase)
Where are monoamines cell bodies located?
DA- SNPC/VTA; Tyr
NE- locus coreolus; Tyr
Epi- brainstem; Tyr
Serotonin- Raphe nuclei; Tryp
Histamine- tuberomammillary nucleus; His
How are cholinergic NTs synthesized?
ACh- synthesized by choline and acetate
Moved into clear vesicles via Vesicular Ach Transporter protein (VAchT)
How are cholinergic NTs degraded?
ACh- removed from synaptic through via acetylcholinesterase bound to post-synaptic cell membrane
What are the receptor characteristics for the Monoamines?
DA- D1, D2, D3
NE/E- Alpha and Beta adrenergics
5-HT: multiple ; 5HT6
Histamine- H1 and H2
What does it mean to say that serotonergic neurons are found in the raphe nuclei?
that is where their cell bodies are found; axons travel to different places
Where is ACh found in the brain?
found a lot in brainstem
on other side of lateral ventricle= basal ganglia- specifically the striatum- CNS (have lot of cholinergic neurons there)
Also found PNS- NMJ, autonomic pregaglionic synapses, PS post-ganglionic fibers, sympathetic post-ganglionic fibers innervating sweatl glands/muscle vasodilators, amacrine cells
What is the striatum in charge of?
control of voluntary motion
What are the midbrain and pons in charge of?
baseline excitation to cortex (brain arousal mechanism), REM sleep
What are the receptor characteristics for the cholinergic NT systems?
MUSCARINIC (metabotropic= serpentine); at least 5 subtypes
NICOTINIC = located at NMJ, synapses bw pre- and post-ganglionic cells in autonomic ganglia; other central synapses; 5 subunits coded for by 16 different genes
What are the subtypes of Acetylcholine receptor M1*?
M1 (neuronal): increase IP3/DAG (Gq)–> increase Ca2+
What are the subtypes of Acetylcholine receptor M4*?
presynaptic autoreceptor; striatum of basal ganglia
decrease cAMP (Gi)
What are the subtypes of Acetylcholine receptor M5*?
cerebrovasculature; dopaminergic neurons of basal ganglia
increase IP3/ DAG (like M1)
What are the subtypes of Acetylcholine receptor M2 and M3?
M2: decrease cAMP (Gi)–> increase K efflux
M3: smooth m. of bronchi, vasculature; endothelial cells of vasc (NO); increase IP3/DAG (Gq) –> increase Ca2+
How are monoamines removed?
- Reuptake by presynaptic terminal
- Two enzymes- MAO and Catchol-Omethyl transferase (COMT*) enzymatic destruction
^For both catecholamines and serotonin
For histamine: diamine oxidase degrades after uptake
What happens if you change the subunits of the nicotinic ACh receptor?
you change the properties of the channel
in some central synapses, it creates a nicotinic channel that allows more calcium in
What are the two major inhibitory AAs?
GABA (y-amino butyric acid) and glycine
What are some characteristics of GABA?
major inhibitory aa NT in CNS
widely distributed through HIGHER levels of CNS: cortex, cerebellum, basal ganglia
spinal cord has least gaba
What is GABA critical in?
consciousness, motor control, vision (retina)
How is GABA synthesized?
from glutamate
Impt enzyme= glutamate decarboxylase (GAD)
also found in pancreatic islet; Abs found in T1D
How is GABA transported into vesicles and removed from synapse?
Transported into vesicles via Vesicular GABA Transporter Protein (VGAT)
removed from synapse via GABA transporter (GAT); NaCl co-transport
two forms = GAT1 (presynaptic terminal) and GAT2 (on glial cells surrounding synapse)`
What happens if GAT1 takes GABA up?
it is on presynaptic terminal; so GABA is repackaged into vesicles as is
What happens if GAT2 takes GABA up?
on astrocytes; glial cell/astrocyte will take up GABA converted to glutamate and will bring it back/convert it to glutamine and released to ECF, where its taken up by presynaptic terminal and recycled into GABA
repackaged and recycled!!
What are the types of GABA receptors?
GABA-A, B, and C
What are the characteristics of GABA-A?
- ionotropic (Cl- conductance)
- activation produces IPSP in adult neurons
- multiple binding sites modulate: benzodiazepine site (sedatives), ethanol, certain steroids, which aLL POTENTIATE action of GABA
- large number of extra-synaptic GABA-A receptors which are believed to be site of action for number of general anesthetics, including propofol
What happens when there is a Cl- influx with GABA around?
Cl-influx –> hyperpolarizes cells normally but Cl- leaves cell when GABA released
What are the characteristics of GABA-B?
-metabotropic, Gi/Go protein coupled
activate a K+ channel (GIRK)–> goes out!! with positive charge produces slow IPSP
close down (inhibit) Ca2+ channel
presynaptically –> regulates NT release
post-synaptically –> inhibition of post-synaptic cell
Where is Glycine found?
spinal cord (major), brainstem (medulla), much less in higher areas of CNS
*almost exclusively on presynaptic side**
What is the function of glycine?
mediates many spinal inhibitions
How is glycine produced and removed from the synapse?
Production: unmodified aa
Removal from synapse by GAT Proteins (same as GABA), recycling
What is the receptor for glycine like?
GlyR: ionotropic (Cl-) like GABA-A
influx of Cl- leads to IPSP
ethanol and general anesthetics bind to it and potentiate
What is an antagonist to the glycine receptor? What symptoms occur with blocking?
Stychnine binds to it and blocks it; prevents channel from opening
Sx: causes convulsions (all activity normally suppressed isn’t being suppressed anymore)
Why are purines long debated?
all synaptic vesicles contain ATP, which led to debate that it was required for metabolic function; some NT synthesis is completed in vesicles; recognized as co-transmitter first
How are purines synthesized and stored in vesicles?
ATP by mitochondria (pre-synaptic terminal has many)
ATP–> ADP–> AMP–> Adenosine occurs in synaptic trough; AMP to adenosine by 5’-nucleosidase
Stored in vesicle (VNUT protein)
Where are purines found?
Virtually everywhere in CNS (especially in CORTEX, CEREBELLUM, HIPPOCAMPUS, BASAL GANGLIA)
What are the purine receptors?
Two major classes: P1 ( A receptors) and P2 (P2X, P2Y)
What are P1 receptors’ ligand and how does function vary for locations?
A receptors
ligand= adenosine
post-synaptic locations= sleep induction; general inhibition of neural function
pre-synaptic locations= inhibition of NT release
What are P2 receptors’ ligands?
P2X receptor- ionotropic; ligand= ATP; many subtypes
P2Y receptor- metabotropic (like P1); ligand= ATP, ADP, UTP, UDP; Gs/Gq coupled
What are the functions of Purines?
Learning and memory (co-release with EAA)
modification of locomotor pathways
Where are peptide transmitters made and transported? via what transport?
NT peptides made in SOMA
transported down AXON via FAST axonal transport
What are the peptide transmitters?
opioids, tachykinins (SP), cholecystokinin, somatostatin, others
What peptides are included in the opioids?
endorphins, enkephalins, dynorphins, and nociceptin
Where are opioids located?
striatum (basal ganglia), hypothalamus, periaqueductal gray, multiple pontine and medullary sites, raphe nuclei in brainstem
What are some general functions of opioids?
modification of nociceptive inputs (cutaneous senses)
-pain relief, mood, and effect
drug addiction/neurophysiology of emotion!!
What are the precursor molecules of opioids?
proopiomelanocortinin (PCOM)–> B- endorphins (from ACTH precursor)
Pro-enkephalin–> Tyr-gly-gly-phe-x (Met or Leu)
Pro-dynorphin –> 3 molecules of Leuk-enkephalin–> Dynorphin
Orphanin FQ–> nociceptin
How are opioids synthesized and removed?
Synthesized by standard protein synthesis in cell body
Removed from trough/cleft by probable reuptake and enzymatic degradation by ENKEPHALINASE and AMINOPEPTIDASE (breaks aa off- thats all needs !)
What receptors do opioids have? what are they?
mu receptors, kappa receptors, and delta receptors
metabotropic (serpentine)–> activate second messenger systems with ligand binding (Gi/Go proteins)
What does activation of the mu opioid receptor cause? Leads to an increase in what?
ANALGESIA, RESPIRATORY DEPRESSION, EUPHORIA, constipation, sedation
Gi (decreased AC)–> leads to an increase in K+ efflux and hyperpolarization
What does activation of the kappa opioid receptor produce?
ANALGESIA and DYSPHORIA mainly
What does activation of the delta opioid receptor produce?
ANALGESIA
What do the kappa and delta opioid receptors do in terms of ions?
decrease Calcium influx
Go= leads to decreased Calcium influx (from decreased IP3/DAG)
What are identified endogenous cannabinoids?
anandamide and 2-arachidonylglycerol (2AG)
What was first identified of endocannabinoids?
exogenous chemicals such as THC- tetrahydrocannabinol
Where are endocannabinoids found?
broadly distributed in CNS
BASAL GANGLIA(mood and motor performance)
SPINAL CORD (modulation of nociception)
CORTEX (neuroprotection)
hippocampus (memory formation)
hypothalamus (control of body energy/hunger- munchies)
How are endocannabinoids synthesized?
derived from membrane lipids (arachidonic acid)
occurs in PRESYNAPTIC TERMINAL
What are the receptors of endocannabinoids?
CB1 and CB2
Why is the CB1 important?
relevant for neurophysiology
found on PRESYNAPTIC terminals of EAA and GABA releasing synapses
reduces EAA and GABA release
Gi coupled protein
Anandamide and 2-AG equally effective!!!
Why is CB2 receptor important? where is it located?
Associated with immune system (Action: anti-inflammatory!!)
located: microglia in barin, gut, immune system in general
* In brain, CB2R activation increases B-amyloid removal *
Which NTs’ receptors are only metabotropic?
Opioids and endocannabinoids
Which NTs’ receptors are only ionotropic?
Glycine
Which Receptors are metabotropic?
nAChR, GABA-B, P1(A), P2Y, Mu,delta,kappa opioid, CB-1
Which receptors are ionotropic?
nAChR, GABA-A, GlyR, P2X
