neurotransmitters františek duška. overview general physiology of synaptic transmission chemical...

Neurotransmitters

František Duška

Overview

•General physiology of synaptic transmission•Chemical division of neurotransmitters

▫Amino acid excitatory: Glu, Asp inhibitory: GABA, Gly

▫Monoamines: Catecholamines: NA, D Serotonin, (melatonin)

▫Acetylcholine▫Peptides▫Others: purines, gases, endogenous cannabinoids

Definice: neurotransmitter, neuromodulatorSynapsisExcitatory and inhibitory postsynaptic potentials

Definitions of terms

•neurotransmitter: ▫a componud secreted into synaptic cleft

and bound to postsynaptic receptors▫removal from synaptic cleft by spercific

biochemical mechanism•neuromodulator:

▫ a compound secreted by neurons into environment and spread by diffusion (or CSF)

▫modulates behavior of other neurons

Postsynaptic membrane•Resting ponential = - 70 mV

▫negative IC, positive EC▫spontaneous depolarization treshold = -55 mV

•Excitatory neurotransmitters EPSP:▫open Ca2+, Na+ channels (influx)▫depolarize = decrease membrane negativity

• Inhibitory neurotransmitters IPSP▫open K+ channels (efflux) or Cl- channels

(influx)▫hyperpolarize = increase negativity

Summatin of postsynaptic potentials

•Neurone: integrates inputs (EPSPs, IPSPs) into output: 0 or 1 (action potential or not)

Summatin of postsynaptic potentials

-synthesis-postsynaptic receptor (receptors)-mechanism of removal from synaptic cleft -clinical and pharmacological significance

Chemical groups of neurotransmitters

Glutamate

•Most cammon excitatory neurotransmitter •Synthesis:

▫from 2-OG (GDH or transaminase)▫deamination of glutamine (glutaminase)

•postsynaptic receptors:▫NMDA (N-methyl-D-aspartát):▫AMPA (α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionate) ▫cainate

Glutamate

•Clinical significance:▫antagonisté NMDA: ketamin (disociativní

anestezie), fencyklidin („angel dust“)▫excitotoxicita▫synaptická plasticita, role v učení and

paměti

Aspartate

•Excitatory neurotransmitter, mostly of spinal cord

•Synthesis▫derived from OAA (citric acid cycle)

•Postsynaptic receptor▫NMDA – lower affinity than Glu

•Removal from synaptic cleft: re-uptake

GABA = γ-aminobutyric acid

•inhibitory neurotransmitter of the brain Synthesis: GABA shunt

GABA: postsynaptic receptors

•GABAA: chloridový channel▫agonisté: benzodiazepiny, barbituráty▫antagonisté: flumazenil

•GABAB: metabotropní rec.G-prototevření K+ channel▫agonista: baclofen

Glycine

•Inhibitory neurotransmitter of spinal cord•Synthesis:

▫from serine•Receptor

▫chloride channel: IPSP▫(co-agonist on NMDA receptors)

•Antagonist = strychnine▫„seizure poison“

Chemical groups of neurotransmitters

Catecholamines: Synthesis

CH2

CH

NH3+

COO- CH2

CH

NH3+

COO-OH CH2

CH

NH3+

OH

OH

COO-

CH2

CH

2

NH3+

OH

OH

CO2CH

CH

2

NH3+

OH

OHOH

CH

CH

2

NH

OH

OHOH

CH3

Phenylalanin Tyrosin 3,4 DihydrOxyPhenylAlanin (DOPA)

+

Adrenalin Noradrenalin Dopamin

1. 2.

3.

4.5.

Catecholamines - Degradation

•Reuptake followed by IC degradation:

•Final metabolite: vanilmandelic acid

CH

77COO-78

OH

CH3OOH

COMT

MAO

Dopamine

•Receptors are metabotropic:▫D1: Gs proteincAMP ion. channel

phosph. EPSP▫D2: Gi protein: phosphodiesterase

activation IPSP

Dopaminergic systems

System Anatomy Function Significance

Mesocortical tegmentumfront. cortex

Motivation, mood, will

Schizophreny

Mesolimbic tegmentum nc. accumbens

dtto Schizophreny, addiction

Nigrostriatal s.nigrastriatum

Motoric system M.Parkinson

Tuberoinfundibular

nc. arcuatus eminent. mediana

Inhibits prolactin secretion

Adverse eff. of antipsychotics

Dopamine – Clinical significance

•Antipsychotics:▫phenothiazines = D-receptor blockers▫AE = parkinsonism, hyperprolactinemia

•Cocaine, amfetamines:▫dopamine re-uptake blockers

•Parkinson disease:▫loss of dopaminergic neurons in

s. nigra. Treatment: L-DOPA

Noradrenaline

•postsynaptic receptors:▫metabotropic: α1, 1 …▫! presynaptic, inhibitory receptors also

exist: α2 •Adrenergic systems:

▫locus coeruleus, lateral tegmentum▫arousal, stress, mood

Serotonin

•= 5-hydroxytryptamin•Anatomy: limbic systém, retikular

formation•Function:

▫anger/aggression, mood, sleep▫appetite/satiety/vomitting▫body temperature▫sexual behavior

Serotonin

•Degradation MAO: 5-hydroxyindolacetate

Melatonine

•Pineal gland•Biorythms•Hormone/neuromodulator

Chemical groups of neurotransmitters

Acetylcholine

•CNS: pontomesencefalotegmental complex▫autonomic NS: preganglionic mediator of

both symp. and p-symp., postganglionic mediator of p-symp

▫peripheral NS: neuromuscular junction•Synthesis: AcCoA + choline:

•Degradation: Acetylcholine eserase

CH2

CH2

O N+

CH3

CH3CH3

CCH3

O

Acetylcholine: postsyn. receptors•Nicotinic = inotropic

▫Na+ channels, neuromuscular junction•Muscarinic = metabotropic

▫M1 = Gq-prot. = K+ current: CNS (cognit. function), autonomic ganglia

▫M2= Gi-prot = K+current: CNS, heart▫M3= Gq: eye, glands▫etc.

Acetylcholine –Clinical significance•Lecithin = phosphatidylcholine as nootropic

agent•Acetylcholine esterase inhibitors:

▫physostigmine (passes through HEB): arousal from general anesthesia

▫neostigmine (does not pass): p-sympatomimetic, myastenia gravis

•M-receptor blockade = atropin▫parasympatolytics

•N-receptor blockade = curare (arrow poison)

Chemical groups of neurotransmitters

Peptides

•Appr. 50 known•Hypothalamus•Synthesis:

▫prepropeptidER, signal sequence cleavage propeptide in vesicles further processing peptide neurotransmitter (1 or more)

•Removal from synaptic cleft:▫Degradation, but not re-uptake

Peptides:

Peptides: examples

•Opioids: endorfines, enkefalins▫limbic system, inhibits l. coeruleus▫axo-axonal synapsis

•NP-Y ▫mediates the influence of leptin on food

intake•Neurotensine:

▫regulates LH and prolactin secretion•substance P…

Chemical groups of neurotransmitters

Others

•Endocannabinoid system:▫retrograde neurotransmission: anandamide

synthesized in the postsynaptic neurone diffuses to presynaptic neurone bound to CB1 and CB2 rec. (G-prot.) influence presynaptic neuron behavior

▫regulates cognitive function, food intake▫THC as illicit drug

Closing remark

•Neurotransmitters cannot cross hematoencefalic barrier

•Chemically identical compounds have many functions aoutside the brain.

•These have not been discussed!!▫catecholamines in regulating blood

pressure and blood flow▫serotonin: immunity▫pituitary peptides…. etc…