Chemical Messengers Flashcards
Inhibitory post-synaptic potentials
small, localized hyperpolarizations usually assoc w/ Cl into cells via ligand-gated Cl channels
make AP less likely
Excitatory post-synaptic potentials
produced by Na or Ca into cell via ligand gated channels
make cell more excitable & increase probability of an AP
Summation
IPSP + EPSP (temporal or spatial)
if brought to threshold, cell will have an AP
Ligand gated receptors
many subunits from many genes
at least 1 subunit binds NT
binding opens pore so ion that selects for can enter cell
metabotropic receptors
large membrane-spanning receptors
coded by 1 gene
ligand binding site on extracell surface
ALL exert post synpatic effects via 1 or more 2nd messenger systems
Gs
activate AC which increases cAMP production
cAMP activates PKA which phosphorylates other proteins
can affect protein synthesis @ level of gene
Gi
inhibit AC so decrease cAMP production & PKA activity
Gq
activate phospholipase C which generates IP3/PIP & DAG
IP3 activates Ca2+ release from intracell Ca2+ stores
Jak Stat pathways
assoc w/ growth & have tyrosine kinase activity upon ligand binding
can then phosphorylate STAT protein which can move to nucleus & activate synthesis of various proteins
Axonal Transport
must move organelles or products for neurotransmission from soma to pre-synaptic terminal
what is transported via fast axonal transport
carry NT vesicles from cell body to synapse
what is transported via slow axonal transport
cytostructural components or ion channels/receptors
what is retrograde transport
movement from synapse to cell body
why is retrograde transport important
crucial to transport neurotrophic substances from synapse back to cell body, can exert trophic effects on neuron or transport used vesicles for degradation
criteria for a chemical to be an NT
neuron releasing the NT contained appropriate synthetic machinery to make NT & contains the NT itself
substance released in chemically or pharmalogically identifiable form
exogenous application of NT reproduces post-synaptic effects seen when presynaptic neuron stimulated naturally
blocking the receptor for the chemical blocks the effects of activating the pre-synaptic neuron
there are mechanisms for deactivating/termination the action of the chemical
Cholinergic System
any synapse that uses Ach as NT of choice
in CNS: critical for consciousness (damage to cholinergic areas leads to comatose state)
5 NTs of Monoamine System
epinephrine, norepinephrine, dopamine, histamine, serotonin
What are the catecholamines & what are they derived from?
dopamine, norepinephrine, epinephrine
all derived from tyrosine
What is norepinephrine assoc w/ in the brain?
waking up from sleep & alerting response
What is dopamine role in brain?
producing pleasure (damage assoc w/ Parkinson’s)
What is histamine role in brain?
from histidine & plays important role in waking you up from sleep
What is serotonin role in brain?
from tryptophan, critical in mood (targeted by anti-depressants)
What are the inhibitory amino acids?
AAs that inhibit neuronal activity
in CNS: glycine & GABA
Glycine location & fxn
found in spinal cord (some in medulla)
produces hyperpolarization by opening CL- channel w/ binding & its release assoc w/ some of spinal cord reflexes that lead to abrupt muscle relaxation if lift something too heavy
GABA location & fxn
found in CNS (in cortex) & can bind 2 receptors
1st receptor assoc w/ Cl- channel=hyperpolarization of membrane
2nd receptor assoc w/ 2nd messenger system
What is the major inhibitory NT in the brain?
GABA (opens a CL- channel where benzodiazepines work to produce sedation)
What are the purine NT system?
ATP & its products (AMP & adenosine)
effect of ATP as NT
usually excitatory
effect of adenosine as NT
mixed effects depending on tissue
linked to sensation of sleepiness/fatigue
how does caffeine work?
antagonist @ adenosine receptors (to keep up awake)
What are the opioid NTs?
group of peptides that bind to opioid receptors @ assoc w/ pain relief
endorphins, enkephalins, dynorphins, nociceptin
How is nociceptin different?
binds to different receptors & actually works to ENHANCE pain inputs under right circumstances
What are the endocannibinoid NTs?
system important in pain relief, involved in control of hunger & energy balance
anandamide
2-AG
Role of NO
second messenger b/c retrograde activity
production tied to activation of excitatory AA receptor (NDMA receptor) b/c Ca2+ influx
NT systems
cholinergic monoamines excitatory AAs inhibitory AAs opioid peptides endocannabinoids
What are the 2 major excitatory AAs in the CNS?
glutamate & aspartate
role of excitatory AAs in CNS
critical to sensory processing, memory formation, learning & motor control
What happens with decrease in O2 in brain?
neurons in brain start to depolarize w/ falling ATP levels
w/ APs, huge amounts of EAA NTs are released @ synapse that uses EAA
excess activation allows huge amounts of Ca2+ to enter post-synaptic cell
What is the problem posed by excess Ca2+ in post-synaptic cell?
Ca2+ can bind to a number of enzymes & change activity level
leads to activation of enzymes that lead to production of NO, damage membrane to release arachidonic acid & hydrolyze proteins & apoptosis
What is the end result of excess Ca2+ in post synaptic cell?
greater neuronal damage than would have been predicted based on original insult
sequence of catecholamine synthesis
tyrosine —>L DOPA—>dopamine—>norepinephrine—>epinephrine
(tyrosine hydroxylase & PNMT)
What is the rate limiting step in catecholamine synthesis?
tyrosine hydroxylase converting tyrosine to L DOPA
Dopamine location in CNS
substantia nigra dopaminergic pathway
mesolimbic dopaminergic pathway
mesocortical dopaminergic pathway
tuberinfundibular pathway
Substantia nigra dopaminergic pathway
controls voluntary motion (damage results to Parkinsons)
Mesolimbic dopamingergic pathway
runs from ventral tegmental area in brain to nucleus accumbens
core of pleasure/reqard pathway in brain (alterations assoc w/ addiction)
Mesocortical dopaminergic pathway
runs from ventral tegmental area to cortex (frontal)
crucial to attention & higher levels of consciousness (dysfunction linked to schizo)
Tuberinfundibular pathway
runs from hypothalamus to anterior pituitary
release of dopamine from these axons suppresses prolactin release from AP
Norepinephrine location in CNS
found in localized cluster of neurons (LOCUS CERULEUS) in upper brainstem (pons)
axons travel to diff parts of cortex & cerebellum for role in waking us up & awareness
Epinephrine location in CNS
only small fraction of neurons (mostly used as hormone released by adrenal medulla)
What are vesicular monoamine transporters (VMATs)?
proteins that move catecholamines into the vesicles that they will be created in & stored in
VMAT1
found in adrenal medulla
moves dopamine into vesicle to be converted to norepi & the epi created in cytoplasm back into vesicles
VMAT2
neuronal form-any neuron that releases monoamines
moves any monoamine into vesicle for synthesis of norepi or storage prior to release as NT
What are both VMAT 1 & VMAT2 sensitive to?
Reserpine (reduces amt of monoamines that are packaged into vesicles)
What receptors do norepi & epi bind to?
alpha & beta adrenergic receptors?
What do D1 & D5 receptors activate?
D1 & D5 bind D1 type receptors that activate Gs proteins
What do D2, D3, and D4 receptors activate
D2, D3, D4 bind D2 type receptors that activate Gi proteins
What is the outcome of D1 & D2 receptor activation and where are they located?
D1: voluntary motion
D2: inhibits motion
receptors found in high conc in regions of brain innervated by substantia nigra
What is the D3 receptor assoc w/?
pleasure & reward system
Mechanism of catecholamine removal from synaptic cleft
reuptake by presynaptic terminal (via high affinity protein)
enzymatic destruction (MAO & COMT)
Monoamine oxidase
found in 2 isoforms in brain for catecholamine destruction
target for drugs for neuropsychiatric disorders
COMT
predominate mechanism in periphery to inactivate epi released by adrenal medulla
also found in CNS (altered function assoc w/ psych disorders)
Enzymes involved in serotonin synthesis
Tryptophan hydroxylase & 5-hydroxytryptophan decarboxylase
Location of serotonergic neurons in CNS
midline raphe nuclei (send axons to cortex of brain & control attention/mood)
What serotonergic receptor is an ionotropic receptor?
5-HT3
What are 5-HT1 receptors associated w/?
Gi proteins
What are 5-HT2 receptors associated w/?
Gq proteins
What are 5-HT3 receptors responsible for?
vomiting elicited by chemotactic trigger zone in meddula
What are 5-HT6 receptors connected with?
high affinity for many anti-depressants
What role do 5-HT2c receptors play?
role in controlling normal body weight & preventing seizures
How is serotonin removed from synaptic cleft?
taken up by process of reuptake & metabolized by MAO
Where are the histaminergic neurons located?
tuberomammillary body in the posterior hypothalamus & sends axons to all parts of CNS (cortex & spinal cord)
What is role of H3 receptor?
feedback that decreases release of histamine from presynaptic terminal
What are the roles of the H1 & H2 receptors?
mediate neuronal effects of histamine assoc w/ wakefulness
How is histamine removed from synaptic cleft?
reuptake system & degradation by diamine oxidase
