Neurotransmitters Flashcards
Overview of neurotransmitters
many are biogenic amines, derived from amino acids by a few simple steps
tyrosine to catacholamines and thyroid hormones
tryptophan to serotonin and melatonin
histidine to histamine
glutamate to gamma-aminobutyric acid (GABA)
Endorphins and enkephlins (opioid activity) are peptide hormones cleaved from proteins
Tyrosine creates ___.
Catacholamines (dopamine, norepinephrine, epinephrine, serotonin) and thyroid hormones
Histidine creates ___.
Histamine (requires pyridoxal phosphate)
Tryptophan creates ___.
Serotonin and melatonin
Glutamate creates ___.
GABA (Gamma-aminobutyric acid)
Reaction types that convert amino acids to neurotransmitters
decarboxylation, hydroxylation, and SAM (methylations)
What maintains the blood-brain barrier?
Astrocytes and microglia
Function of astrocytes
Phagocytosis of debris, nutritional support for neurons (lactate)
Astrocytomas
most common supratentorial intra-axial tumor in all age groups and the most common brain tumor in children
microglia function
“macrophages of brain”, immunologically responsive
Xenobiotics are pumped out by ____. (blood-brain barrier question)
ABC transporters
What are some things that can cross the blood-brain barrier?
essential fatty acids, glucose, (xenobiotics pumped out by ABC transporters)
What are some things that cannot cross the blood-brain barrier?
Non-drowsy antihistamines, non-essential fatty acids
What are the glucose receptors related to the blood-brain barrier?
GLUT1 is used by endothelial cells. GLUT3 is used by neurons
Examples of neurotransmitters
Glutamate and aspartate: major excitory neurotransmitters (cortex, cerebellum, spinal cord)
GABA: major inhibitory neurotransmitter in the brain
Serotonin: affects mood, sleep, apetite (regulated by tryptophan uptake and monoamine oxidase degradation)
Acetylcholine: neurotransmitter primarily for motor neurons
Norepinephrine: stress hormone (released by tyrosine hydroxylase and monoamine oxidase)
Glutamate and aspartate
major excitory neurotransmitters (cortex, cerebellum, spinal cord)
GABA
major inhibitory neurotransmitter in the brain, from glutamate
Serotonin
affects mood, sleep, apetite (regulated by tryptophan uptake and monoamine oxidase degradation)
Regulates sleep, temperature, and blood pressure
Powerful vasoconstrictor and stimulator of smooth muscle
Acetylcholine
neurotransmitter primarily for motor neurons
Norepinephrine
stress hormone (released by tyrosine hydroxylase and monoamine oxidase)
Catecholamine examples
dopamine, norepinephrine, epinephrine
Functions of catecholamines
fight or flight response
bind alpha and beta adrenergic receptors
alter intracellular concentrations of calcium and cAMP
General affects of catecholamines
increase glycogen degradation and release of glucose into the blood
increase triglyceride hydrolysis and release of fatty acids from adipose tissue
increase release of glucagon from pancreatic alpha cells
increase glycogen degradation in muscle
Rate-limiting step of formation of catecholamines
tyrosine hydroxylase
Regulation of catecholamines
rate limiting step is tyrosine hydroxylase
feedback inhibition by dopamine and norepinephrine
activated by cAMP-dependent phosphorylation
Metabolized rapidly. Short half lives (15-30 seconds). Inactivated by 2 enzymes (Catecholamine-O-methyltransferase or COMT and Monoamine oxidase or MAO) to form vanillylmandelic acid (VMA)
Epinephrine
Tyrosine derivative hormone (catecholamine)
made in adrenal medulla and sympathetic nerve endings
binds beta2-adrenergic receptors –> G proteins –> cAMP increase –> phosphorylation (PKC + Calcium)
Responsible for rapid mobilization of energy and glucose
Fight or Flight: immediate increase in blood glucose through liver and muscle glycogenolysis
Difference between epinephrine and norepinephrine
Norepinephrine has amine group on end, epinephrine has methyl group on end
Where is epinephrine made?
in the adrenal medulla and sympathetic nerve endings
Defective tyrosine hydroxylase in melanocytes leads to ____.
Albinism
dopa decarboxylase requires ___ as a cofactor.
PLP (vitamin B6, pyridoxine)
Dopamine beta-hydroxylase requires ___ as a cofactor.
Vitamin C
Phenyl-ethanolamine N-methyl transferase requires ___ as a cofactor.
SAM (S-adenosyl methionine)
Dopa decarboxylase makes ___ from ___.
dopamine from dopa
Dopamine beta-hydroxylase makes ___ from ___.
norepinephrine from dopamine
Phenyl-ethanolamine N-methyl transferase makes ___ from ___.
epinephrine from norepinephrine
Pheochromocytoma
Catecholamine-secreting tumor
Adrenal gland tumor
Excessive secretion of norepinephrine or epinephrine
May precipitate life-threatening hypertension or cardiac arrythmias
Symptoms include headache, palpitations with severe hypertension (worsen with time)
Rare
diagnostic test: elevated metanephrine in urine
How do you test for pheochromocytoma?
elevated metanephrine in urine
Catecholamine inactivation
monoamine oxidase converts norepinephrine or epinephrine to 3-methoxy-4-hydroxymandelic acid (or VMA, vanillylmandelic acid)
They also have an oxidation step. Norepinephrine has a step that uses SAM/COMT.
Parkinson’s disease
caused by a degeneration of dopamine producing neurons in the substantia nigra
Lewy bodies also present
Decreased motor cortex stimulation by basal ganglia
Levodopa can treat it
Carbidopa used in conjunction to inhibit L-amino acid decarboxylase in peripheral tissues (it cannot cross the blood-brain barrier)
Melatonin is a product of __.
Serotonin
Serotonin synthesis requires ___.
BH4 (and tryptophan and oxygen)
tyrosine hydroxylase also requires BH4
Melatonin is produced by the ___.
pineal gland
Melatonin synthesis requires __.
SAM and Acetyl CoA
Examples of selective serotonin reuptake inhibitors
prozac, fluoxetine, zoloft, and celexa
Serotonin syndrome
Use of serotonin reuptake inhibitors and monoamine oxidase inhibitors together causes this
Symptoms: cognitive behavior such as confusion, disorientation, neuromuscular such as muscle spasms, and autonomic nervous system including fever, sweating, and high blood pressure
93 deaths estimated in 2002
Histamine
Chemical messenger formed from histidine (requires pyridoxal phosphate)
Causes allergic and inflammatory reactions
Released from mast cell present in thalamus, dura mater leptomeninges and choroid plexus
Powerful vasodilator of blood vessels, expand capillaries,, localized edema, drop in blood pressure
Lungs: constricts bronchioles
Stomach: stimulates HCl secretion
in the Brain: Neurotransmitter
Activates postynaptic and presynaptic receptors
removed by astrocytes
believed to have role in sleep regulation
What is the end product of histamine inactivation?
In peripheral tissues, it is imidazole acetic acid. In the brain, it is methylimidazole acetic acid. The brain converts histamine to methylhistamine
Acetylcholine is broken down into ___ by ___.
acetic acid and choline, by acetylcholinesterase
Choline synthesis requires ___ (donated by SAM) to phosphatidylethanolamine.
3 methyl transfers
Acetylcholine activates ____.
muscarinic receptors
Acetylcholinesterase inhibitors
Sarin and parathion
Antidote to acetylcholinesterase inhibitors
Atropine (blocks access to the muscarinic receptors)
How are some patients with myasthenia gravis treated?
They are given pyridostigmine to inhibit acetylcholinesterase, which helps make up for the lack of acetylcholine receptors
Nitric oxide
Free radical diatomic gas that can diffuse through membranes
half life is seconds
Arginine + NADPH —> citrulline + nitric oxide + NADP+
Cofactors of nitric oxide synthase
Contain FAD, FMN, and cytochrome-like heme prosthetic groups in a single polypeptide chain
Three genes identified for NOS isoforms
Neuronal NOS-I: activated by NMDA receptor stimulation (Glu)
Cerebral blood flow, smooth muscle relaxation
(Viagra inhibits cGMP phosphodiesterase 5, enhancing smooth muscle relaxation, blood flow, male erection)
Macrophage or induced (NOS-II)
Endothelial (NOS-III), constitutive
Mechanism of nitric oxide
enters the smooth muscle, stimulates guanylate cyclase to produce cGMP which results in smooth muscle relaxation (blood vessel dilation)
What does Viagara do?
Viagra inhibits cGMP phosphodiesterase 5, enhancing smooth muscle relaxation, blood flow, male erection
Refsum’s disease
build up of phytanic acid (chlorophyll) in peroxisomes. Lack hydroxylation enzyme for degredation
Mucopolysaccharidoses
Group of inherited metabolic disorders caused by a deficiency in one of the specific lysosomal enzymes needed to break down mucopolysaccharides
Period of normal development followed by a decline in physical and/or mental function
Hurler syndrome
mucopolysaccharidoses in which alpha-iduronidase is deficient. Results in accumulation of glycosaminoglycan, heparan, and dermatan sulfate. Has corneal clouding.
Hunter syndrome
mucopolysaccharidoses in which Iduronate sulfatase (required for degredation of sugar linkages) is deficient. Glycosaminoglycan, heparan, and dermatan sulfate accumulate. Does not have corneal clouding.
Glycoprotein synthesis
N-glycosylation of proteins is more complex than o-glycosylation.
Oligosaccharides are assembled on membrane bound dolichol phosphate.
Dolichols consist of long poly-isoprene units
Glycoproteins
Sugar chains, often branched, do not have repeating disaccharides
Excludes proteoglycans
Found in most blood proteins, ECM proteins: collagen. Secretions of mucus-producing cells, cell surface proteins (blood groups), lysosomal and ER membrane associated proteins
Glycolipids
lipid sphingosine + sugars
cerebrosides, sulfatides, globosides, gangliosides (have at least one sialic acid (NANA) residue)
Polar head group (sugars) is attached to ceramide by a glycosidic bond at the terminal hydroxyl of sphingosine
Ganglioside have at least one ____ residue.
sialic acid (NANA)
Defective protein in Farber’s diease
ceramidase
Defective protein in Gaucher’s disease
glucocerebroside
Defective protein in Krabbe’s disease
galactocerebroside
Defective protein in Tay-Sach’s disease
hexosaminidase A
Defective protein in Neimann-Pick disease
Sphingomyelinase
Defective protein in Gm1 gangliosidosis
GM1-beta-galactosiase
Product accumulated in Gaucher’s disease
glucosylceramide
Accumulation of glycosphingolipids indicates ___.
Fabry disease
Accumulation of GM2 ganglioside indicates ____.
Tay-Sach’s disease
Product accumulated in Farber’s disease
Sphingosine ceramide
Gaucher’s disease
Cause by buildup of glucosylceramide and defective glucocerebroside. Hepatosplenomegaly occurs. Diagnostic lipid-laden macrophages (“crinkled paper appearance”) termed Gaucher cells are present
