Download Neurotransmitters

Neurotransmitters
Reference: Devlin Ch 23
Selective reading!
MOHAMAD NUSIER, M.D., Ph.D.
Neurotransmitters
1. Excitatory:
1. Acetylcholine
2. Chatecholamines
2. Inhibitory:
1. Glycine* (acts in spinal cord & brain stem)
2. GABA* (acts in all other parts of brain)
3. Taurine
* Major ones
•
1.
2.
•
The biogenic amines: indolamines
Serotonin
Histamine
The amino acid transmitters:
1. Glutamate
2. GABA
3. Glycine
Acetylcholine
• Synthesized in terminals from
acetyl CoA (found everywhere) and
choline (from blood and recycled
ACh, but not synthesized in
neurons)
• Synthesizing enzyme = CAT
(choline acetyl transferase)
Acetylcholine
Inactivated = by ACHesterase; ACh is
not taken up into neurons
Used by somatic motor neurons within
CNS
Two major subtypes of receptors =
nicotinic (nAChR) and muscarinic
(mAChR), each of which has its own
subtypes
Acetylcholine
nAChRs are directly gated channels for
Na+ and K+
nAChRs are found on striate muscle
(N1), postganglionic neurons (N2); CNS.
mAChRs are linked to 2nd messengers
mAChRs are found on visceral smooth,
cardiac muscle, glands, postganglionic
neurons, CNS
Dopamine
• Is a biogenic amine & specifically a
catecholamine, so it shares a pathway with
NE & EPI
• Synthesized from tyrosine (Tyr is from the
essential AA Phe)
• Rate limiting enzyme is
tyrosine hydroxylase
• Carbidopa blocks conversion of DOPA
(dihydroxyphenylalanine) to dopamine by
dopa decarboxylase, but cannot cross the
BBB
• Inactivation: reuptake (blocked by cocaine);
degradation by COMT (extracellular) and by
MAO (intracellular)
• A major metabolite: HVA (homovanillic acid)
which shows up in CSF
• So far, there are 5 subtypes known, all 2nd
messenger-linked
• DA is important in mood disorders,
schizophrenia, basal ganglia function
• Parkinson's results from loss of DA neurons
in basal ganglia
Norepinephrine
• Shares pathway with other
catecholamines (Dopamine)
• Used in CNS (locus coeruleus
and lateral tegmental nuclei of
brainstem) and by most postganglionic sympathetic neurons
• Inactivation = reuptake (blocked by
cocaine); degradation by COMT in
extracellular space and by MAO
(intracellular)
• At least 4 subtypes, all 2nd
messenger-linked. (b1,b2 increase
cAMP, a2 decreases cAMP, að1 acts
through PLC)
• Agonists include ephedrine,
phenylephrine (a), isoproterenol (b)
• Antagonists include phentolamine
(a), propranolol (b)
Epinephrine
• A transmitter in a few brain
stem neurons
• an adrenal neurohormone
Synthesis of catecholamines
Serotonin (5HT = 5hydroxytryptamine)
• Synthesized from tryptophan
• Rate-limiting enzyme = tryptophan
hydroxylase
• Inactivation = reuptake into terminals,
degradation by MAO
• The raphe nuclei of the brain stem are
the major source of 5HT
• raphe nuclei are midline, i.e. unpaired
nuclei
• Many subtypes, many actions
• Mostly 2nd messenger-gated, but at
least one direct channel receptor
• Many anti-depressants are targeted at
5-HT neurons (the popular prozac)
Histamine
• A local hormone and a
hypothalamic transmitter
• At least three receptor subtypes
known so far
• Synthesized from histidine
Glutamate
• Mediates fast excitatory
communication in the CNS (direct
channel-linked)
• Acts through three direct ligandgated channel receptor types:
NMDA , AMPA and kainate (KA)
receptors,
• And through two or more types of
metabotropic (G-protein linked)
receptors (ACPD and L-AP4)
Glutamate
• NOTE: The names reflect their different
pharmacological profiles, but
physiologically, in the body, they all bind
glutamate
• NMDA receptor channels admit Ca ++
which can have important 2nd messenger
effects
• GLU is an abundant amino acid in the
brain, maybe 30% of which is transmitter
• Inactivation = reuptake by glia, conversion
to glutamine, return to neuron terminal
(where it can be reconverted to Glu)
Glutamate
• Glu is synthesized by 3 methods:
1. Deamination of Glutamine by glutamase
2. Amination of alpha ketoglutarate by Glu
dehydrogenase utilizing free ammonia
3. Transamination of alpha ketoglutarate by
transaminase
GABA
• Major inhibitory transmitter in the CNS
• Altered GABAergic function may play a role
in many clinical situations (e.g. basal ganglia
disorders, seizure disorders, schizophrenia,
sleep disorders)
• Synthesized from glutamate by GAD
(glutamic acid decarboxylase)
• Inactivation = reuptake by nerve terminals for
reuse and by glia, where it undergoes
conversion to glutamine, return to neuron
terminal (where it can be reconverted to Glu
and then to GABA)
GABA
• At least two major receptor subtypes:
• GABAA is a direct-gated Cl- channel
• GABAB is G-protein linked, inhibited by
increasing K+ permeability, decreasing
Ca++ influx (especially as presynaptic
inhibition), decreases cAMP
• Benzodiazepines (Valium) and,
probably, neurosteroids bind to GABAA
receptor, increase GABA effect
• Agonists: Muscimol (A), baclofen (B)
• Antagonists: Bicuculline (A)
Glycine
• The other inhibitory transmitter in the
CNS
• Receptor is direct ligand-gated Clchannel
• Used by Renshaw cells (inhibitory
interneurons in spinal cord, supplying
recurrent inhibition)
• Antagonist = strychnine
GABA and Glycine
• Most inhibitory neurons use one or the other.
• Inhibits the ability to fire action potentials.
• GABA made from glutamate by glutamic acid
decarboxylase (GAD), requires Vit B6 as cofactor.
B6 deficiency can lead to loss of synaptic
transmission.
• Receptors: GABAa and GABAb
• Implicated in epilepsy
• Glycine- about 1/2 of neurons in spinal cord use
glycine, receptors similar to GABAa receptors
• Both GABA and glycine are rapidly taken up by
glia and neurons.
• Hyperglycinemia- defect in glycine uptake and
removal leads to severe mental retardation.
Aspartate
• Similar to glutamate: excitatory
NT
• Functions in fewer pathways
• Made from oxaloacetate by
tranamination reaction
• Aspartate can not pass through
BBB
Nitric
Oxide
• Effects: vasodilatation,
neurotransmission (penile
erection), killing tumor cells and
parasites
• Made from arginine by Nitric
Oxide synthase
• NO activates guanylate cyclase:
increase cGMP: activates protein
kinases
• Can cross membranes (gas)
Synthesis, Release, and Reuptake of the Inhibitory
Neurotransmitters GABA and Glycine
Vesicular
transporters
regulate the
amount and
type of
neurotransmit
ter
sequestered
into synaptic
vesicles
Synthesis, Release, and Reuptake of the Inhibitory
Neurotransmitters GABA and Glycine
• Phenylketonuria (PKU)
• This is one of the most common inborn
errors of metabolism which affects cerebral
activity, affecting approximately 1 out of
20,000 infants. The defect is a lack of
phenylalanine hydroxylase and leads to
increased concentrations of phenylalanine.
The neurochemical mechanisms involve
tyrosine and tryptophan pathways.
Fortunately, the disorder can be treated in
many cases by diet restriction.
• Tay Sachs Disease
• This is a lipid-storage disorder transmitted as
an autosomal recessive trait. The metabolic
defect is a deficiency of the hexosaminidase
found in lysosomes involved in ganglioside
degradation. Its absence causes lipids and
proteins to accumulate in membranous
cytoplasmic bodies. There is no established
therapy, although recent research has
searched for a means of enzyme
replacement.