Synaptic receptors, neurotransmitters and brain modulators, energetical brain metabolism, barrier CNS mechanisms Romana Šlamberová, MD PhD Department of.

Synaptic receptors, Synaptic receptors, neurotransmitters and brain neurotransmitters and brain

modulators, energetical brain modulators, energetical brain metabolism, barrier CNS metabolism, barrier CNS

mechanismsmechanisms

Romana Šlamberová, MD Romana Šlamberová, MD PhDPhD

Department of Normal, Pathological and Clinical

Physiology

NeuronNeuron

Kandel: Principles of Neural Sciences

MacrogliaMacroglia

Kandel: Principles of Neural Sciences

Synapse 1Synapse 1

Synapses Chemical – secreting neurotransmitters Electrical - direct opening of fluid channels that conduct electricity from one cell to another (gap junction)

Synapse 2Synapse 2

The human brain contains a huge number of synapses. Young children have about 1,000 trillion. This number declines with age, stabilizing by adulthood.

Estimates for an adult vary from 100 to 500 trillion synapses.

The word "synapse" comes from "synaptein" which Sir Charles Scott Sherrington and his colleagues coined from the Greek "syn-" meaning "together" and "haptein" meaning "to clasp".

Synapse 3Synapse 3

Synapses are specialized junctions through which cells of the nervous system signal to one another and to non-neuronal cells such as muscles or glands.

Synapses allow the neurons of the central nervous system to form interconnected neural circuits. They are crucial to the biological computations that

underlie perception and thought. They provide the means through which the nervous

system connects to and controls the other systems of the body.

Transmembrane receptorTransmembrane receptor

Types of receptors 1Types of receptors 1

Ionotropic receptors (Ligand-gated ion channels) Voltage-gated ion channels - activated by the

surrounding potential difference (ions can travel down their electrochemical gradients – Na+, K+)

Stretch-gated ion channels - open their pores in response to mechanical deformation of a neuron's plasma membrane

Types of receptors 2Types of receptors 2

Metabotropic receptors monomeric proteins with seven transmembrane domains.

The protein's N terminus is on the extracellular side of the membrane and its C terminus is on the intracellular side.

First messenger = ligand that binds to the receptor Second messenger

G-proteins - molecular "switch" to allow or inhibit biochemical reactions inside the cell [exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP)]

Tyrosine kinase - enzyme that can transfer a phosphate group to a tyrosine residue in a protein (Phosphorylation is an important function in signal transduction to regulate enzyme activity.)

NeurotransmittersNeurotransmitters

= chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell.

Talking about NT - if it respects the following conditions: It is synthesized endogenously, that is, within the

presynaptic neuron It is available in sufficient quantity in the presynaptic neuron

to exert an effect on the postsynaptic neuron Externally administered, it must mimic the endogenously-

released substance A biochemical mechanism for inactivation must be present

Types of Types of neurotransmittersneurotransmitters

Biogenic amines Acetylcholine (Ach)

Amino acids Aspartate Glutamate (Glu) γ-Aminobutyric acid

(GABA) Glycine (Gly)

Monoamines Catecholamines (from

phenylalanine and tyrosine)

Dopamine (DA) Norepinephrine (NE) Epinephrine (Epi)

From tryptophan: Serotonin (5-HT) Melatonin (Mel)

From histidine: Histamine (H)

Acetylcholine Acetylcholine

In PNS and CNS Acetylcholine is synthesized in certain neurons by

the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA.

shortage of acetylcholine in the brain has been associated with Alzheimer's disease

ACH receptors nicotinic acetylcholine receptors (ionotropic) are particularly

responsive to nicotine. Located in the CNS and preganglionic parts of autonomic system.

muscarinic acetylcholine receptors (metabotropic) are particularly responsive to muscarine. Located in the CNS and postganglionic parts of autonomic system.

MuscarinMuscarin

Fly agaricAmanita muscaria from which muscarine was isolated

Glutamate (Glutamic acid)Glutamate (Glutamic acid)

Most abundant excitatory neurotransmitter in the nervous system.

In excess, glutamic acid triggers a process called excitotoxicity, causing neuronal damage and eventual cell death, particularly when NMDA receptors are activated (epilepsy).

It’s overstimulation occurs as part of the ischemic cascade and is associated with diseases like amyotrophic lateral sclerosis and Alzheimer's disease.

Receptors: Ionotropic – NMDA; non-NMDA (AMPA, Kainate) Metabotropic

Gamma-aminobutyric acid Gamma-aminobutyric acid (GABA)(GABA)

Most important inhibitory neurotransmitter in the CNS.

Acts as a transmitter, the inhibition results from a hyperpolarization of the transmembrane potential of the inhibited neuron.

Receptors: GABA A – ionotropic – Cl-

GABA B – metabotropic - via G-proteins to potassium channels

GABA C – as GABA A (Cl- ) but slow response

Dopamine Dopamine

In the brain, dopamine functions as a neurotransmitter

DA is also a neurohormone released by the hypothalamus.

Functions of dopamine in the brain: Role in movement (basal ganglia) Role in cognition and frontal cortex function (frontal lobe

and prefrontal area) Role in pleasure and motivation (nucleus accumbens,

striatum) Pathophysiology - psychosis and schizophrenia Therapeutic use – L-DOPA – Parkinson’s disease

SerotoninSerotonin

In the CNS - important role in the regulation of mood, sleep, emesis (vomiting), sexuality and appetite.

5-HT has been thought to play a part in many disorders, notably as part of the biochemistry of depression, migraine, bipolar disorder and anxiety.

A variety of psychiatric and neurological medications affect serotonin levels: Antidepressants Antiemetics

NeuromodulatorsNeuromodulators

A neuromodulator is a substance other than a neurotransmitter, released by a neuron at a synapse and conveying information to adjacent or distant neurons, either enhancing or damping their activities.

Neuromodulators modulate regions or circuits of the brain. That is, they affect a group of neurons, causing a modulation of that group.

Their action can be described as a neuron-neuron exchange of information, rather than an action on specific postsynaptic neurons.

Blood-brain barrier Blood-brain barrier 1 1

Membrane that controls the passage of substances from the blood into the central nervous system (tight junctions)

The blood-brain barrier blocks all molecules except those that cross cell membranes by means of lipid solubility (such as oxygen, carbon dioxide, ethanol) and steroid hormones, and those that are allowed in by specific transport systems (such as sugars and some amino acids).

Function - protects the brain from the many chemicals flowing around the body and agains infection.

A major challenge for treatment of most brain disorders is overcoming the difficulty of delivering therapeutic agents to specific regions of the brain.

Blood-brain barrier Blood-brain barrier 2 2

Cerebrospinal fluid 1Cerebrospinal fluid 1

Clear bodily fluid that occupies the subarachnoid space in the brain and the ventricular system of the brain and the spinal cord.

Produced by the choroid plexus and the ependymal lining of the brain's ventricles.

Circulates through the interventricular foramina into the third ventricle and then via the mesencephalic duct (cerebral aqueduct) into the fourth ventricle space through two lateral apertures and one median aperature and is then absorbed by the venous system to the blood circulation.

total amount of cerebrospinal fluid is about 150 ml, and about 500 ml is produced every day, which indicates its very active circulation.

Cerebrospinal fluid 2Cerebrospinal fluid 2

Choroid plexusChoroid plexus

Area on the ventricles of the brain where cerebrospinal fluid (CSF) is produced.

Present in lateral, third and fourth ventricles. Consists of many capillaries, separated from the

subarachnoid space by pia mater and choroid ependymal cells.

Liquid filters through these cells from blood to become CSF. There is also much active transport of substances into, and out of, of the CSF as it's made.

Easiest passable part of the blood-brain barrier.

Metabolism of brainMetabolism of brain

Brain metabolism depends on glucose. Prolonged neuroglycopenia can result in

permanent damage to the brain. Brain cells are extremely sensitive to oxygen

deprivation and can begin to die within five minutes after oxygen supply has been cut off.

When hypoxia lasts for longer periods of time: Coma Seizures Brain death