Download Neurotransmitter Location in Brain Synthesis and storage Receptors

Neurotransmitter
Location in Brain
Synthesis and storage
Catecholamines:
Norepinephrine (NE)
-locus coeruleus & other parts
of RAS --project rostrally to the
hypothalamus, hippocampus,
amygdale, and cerebral cortex
-project dorsally to cerebellum
-project caudally to lower
brainstem and spinal cord
-LC acts as filter to suppress
irrelevant stimuli?
-in nerve terminal
-tyrosineDOPA
dopamineNE using:
-tyrosine hydroxylase: rate
limiting; inhibited by α-methylp-tyrosine
-aromatic L-amino acid
decarboxylase
-dopamine-β-hydrogenase: on
luminal surface of vesicles;
nonspecific, false nt
-uneven, 80% in striatum, cell
body clusters in midbrain
-4 pathways:
1.)nigrostriatal: cell body in
substantia nigra and axons that
project to daudate-putamen
2.)mesolimbic pathway with
bodies in ventral tegmental
and axons to limbic structures
(accumbens, hippo, lateral
septum, amygdale
3.) mesocortical path with
bodies in VTA and axons in
cerebral cortex
4.)tuberoinfundibular path w/
bodies in arcuate nucleus of
hypthal and proj to pituitary
salk, where tonically inhib
prolactin
tyrosine->DOPAdopamine
Catecholamines: Dopamine
Receptors and Signal
Transduction
α1: coupled to Gq to stimulate
phospholipase C; also cAMP;
neuronal
-α2:coupled to Gi to inhibit
adenylate cyclase; glial and
vascular
-β1 &β2: both ↑cAMP including
presyn β2 which facilitate NE
release. β2 have ↑affinity for
EPI than for NE, thus EPI
regulates NE
Inactivation
-D1-D5: all metabotropic and
act on G proteins
-1 & 5=excitatory and ↑cAMP
by acting on Gs
-2,3,4=inhibitory and ↓cAMP
via Gi
-2= enhance K+ channel
opening =hyperpolarization
-dopamine transporter
-MAO and COMT
-main metab= HVA
-reuptake:
- NE transporter = uptake 1
-uptake 2 = glial cells
-enzyme degradation:
-monoamine oxidase
(mitochondrial outer
membrane) – phenelzine and
tranycypromine – inhibit both
MAO-A and MAO-B
-COMT- extraneuronal
catecholamine metab
metab=VMA, MHPG
Acetylcholine (Ach)
Serotonin (5-HT)
GABA
Location in Brain
Synthesis and Storage
-bodies in nucleus basalis and a
few other regions w/ axons in
cerebral cortex, hippo, and other
limbic areas via basal forebrain
cholinergic system
-cholinergic interneurons in
striatum that reg motor f’n;
inhibitie by nigrostriatal DA
neurons and lead to Park’s sx
when DA inhib deficient
-bodies midline of brainstem in
clusters called dorsal and medial
raphe nucleus
-axons: neocortex, striatum,
accumbens, thala, hypothal,
hippo, amygdale, spetal area
-via choline acetyltransferase:
choline + acetyl CoAAch
-40% terminals in cerebral
cortex, hipp, and substantia
nigra
-in cortex and hipp mainly in
interneurons
-proj from striatum to golus
pallidus and substania nigra
-uptake and storage in vesiclesthe Ach transporter is located in
an intron of the choine acetyltransferase gene and thus
synthesis and storage are
coupled
tryptophan 5hydroxytryptophan  5hydroxytryptamine (5-HT)
-1st catalyzed by tryptophan
hydroxylase= rate limiting
-2nd L-aromatic amino acid
decarboxylase
storage: vesicles using same
monoamine transporter
(VMAT2) as catecholamines
glutamateGABA via glutamic
acid decarboxylase
storage: taken up into vesicles
via vesicular GABA transporter
VGAT
Receptors and Signal
Transduction
-nicotinic receptors (Nn more
sensitive in brain than Nm in
neuromusc j’n)
-muscarinic M1-5- all metabot
-some activate phosphoinositide
2nd mess sys, inhibit cAMP, or
stim K+ opening
-high density in forebrain
-release regulated by terminal
and somatodendritic 5HT
autorecpetors
Inactivation
acetylcholinesterase
-modulation by drugs: choline
transporter blocker; blocker of
acetyl CoA synthesis; inhibi of
vesicular transporter; Ca++
transport; vesicle-dock blockers;
cholinesterase inhibitors
reuptake back in presyn nerve
terminal via transporter SERT
catabolism by MAO
-15 receptors known
-all metab exept 5HT3
-GABAa: inonotropic, Cl channel,
when openhyperpolar.
-GABAb:metabo, inhibit cAMP
and open K+
-modulation
-drugs:HT1 agon=buspirone; LSD
by 2a; atypical antipsy via 2a
-diet: low protein/high carb
↑5HT
-reuptake into nerve terminal
via GAt-1
-GAT-2 and -3 into glia
-in both some broken down by
GABA transaminase to glutamate
and can be reconverted
modulation:
-benzo, barbit, etoh=sedation
GABAa
-vigabatrin irrev inhibi of
metabolism
-baclofen= agonist GABAb
Glutamate
Location in Brain
Synthesis and storage
-pyramidal cells of cerebral
cortex that proj to subcortical
structures such as striatum, thal,
limbic areas and brain stem
-mainly from glutamine
Neuropeptides
-storage: vesicles
-3 vesicular transporters:
VGLUT1-3 promote packaging
into vesicles
-synth in ribosomes in bodies
and transported to terminal in
large dense-cored vesicals via
fast axonal transport
-reg of synth = slow
-small amt in terminal
-receptors gen require low conc
and removal is slow
Receptors and Signal
Transduction
-both iono and metabo
-aka AA receptors sinc aspartate
works too
-3 types iono (all exite):
-AMPA – depol via Na+into cell
-kainate – depol via Na+into cell
(epilepsy)
-NMDA – depol via Na & Ca++
into cell (schizophren)
-metabotropic activating G-prot
-co-released with small nt
-acts as co-transmitter
-f’n of peptide to
↑time/strength of signal, but no
effect itself=neuromodulator
-release of some is freq dep
-Corticotropin-releasing
hormone (CRH)
-Substance P
-Opioid Peptides
-41aa peptide
-paraventricular nucleus PVN of
hypthal
-neuroendo f’n
-11aa neuropeptide
-tachykinin family
-wide distrib, hypthal, corpus
strit to nigra
-family derived from 267 aa long
precursor propiomelancortin
(POMC
-syth from precursor peptides
that are cleaved to active
neropep
-in the PVN is released into
pituitary portal capillaries
causing co-release of ACTH and
β-endorphin during stress respo
-released from afferent sensory
neurons in spinal cord to
transmit painsignals
-endogenous peptides
-endorphins
-CRH1=dominates pituitary
-CRH2
-NK1-3
-1 on 5Ht, DA, and NE neurons
and have been found to have
anti depressant effects
-βendorphin most potent
-CRF causes large ↑in release of
POMC from pituitary gland with
subsequent ↑ACTH and
βendorphin
Inactivation
-reuptake via 5 excitatory AA
transporters (EAAT1-5) which
also do aspart
-mod: MSG can damage by
excitotoxicity; PCP and ketamine
are NMDa antagonists
-diffusion & proteolysis
-not recycled
-cleaved molc may have postsyn
effect