1. Reference: Devlin Ch 23 Selective reading! MOHAMAD NUSIER, M.D., Ph.D.
Neurotransmitters
Reference: Devlin Ch 23
Selective reading!
MOHAMAD NUSIER, M.D., Ph.D.

2. Neurotransmitters Excitatory: Inhibitory: Acetylcholine
Chatecholamines
Inhibitory:
Glycine* (acts in spinal cord & brain stem)
GABA* (acts in all other parts of brain)
Taurine
* Major ones

3. The biogenic amines: indolamines Serotonin Histamine
The amino acid transmitters:
Glutamate
GABA
Glycine

4. 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)

5. 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

6. 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

7. 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

8. 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

9. Norepinephrine Shares pathway with other catecholamines (Dopamine)
Used in CNS (locus coeruleus and lateral tegmental nuclei of brainstem) and by most post-ganglionic sympathetic neurons

10. 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)

11. Epinephrine A transmitter in a few brain stem neurons
an adrenal neurohormone

12. Synthesis of catecholamines

14. Serotonin (5HT = 5-hydroxytryptamine)
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

15. 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)

17. Histamine A local hormone and a hypothalamic transmitter
At least three receptor subtypes known so far
Synthesized from histidine

19. Glutamate
Mediates fast excitatory communication in the CNS (direct channel-linked)
Acts through three direct ligand-gated 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)

20. 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)

21. Glutamate Glu is synthesized by 3 methods:
Deamination of Glutamine by glutamase
Amination of alpha ketoglutarate by Glu dehydrogenase utilizing free ammonia
Transamination of alpha ketoglutarate by transaminase

22. 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)

23. 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)

24. Glycine The other inhibitory transmitter in the CNS
Receptor is direct ligand-gated Cl- channel
Used by Renshaw cells (inhibitory interneurons in spinal cord, supplying recurrent inhibition)
Antagonist = strychnine

25. 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.

26. Similar to glutamate: excitatory NT Functions in fewer pathways
Aspartate
Similar to glutamate: excitatory NT
Functions in fewer pathways
Made from oxaloacetate by tranamination reaction
Aspartate can not pass through BBB

27. 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)

28. Synthesis, Release, and Reuptake of the Inhibitory Neurotransmitters GABA and Glycine
Vesicular transporters regulate the amount and type of neurotransmitter sequestered into synaptic vesicles

29. Synthesis, Release, and Reuptake of the Inhibitory Neurotransmitters GABA and Glycine

30. 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.

31. 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.