Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

SIGNALING IN THE NERVOUS SYSTEM

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

Presynaptic neuron (axon terminal)

Postsynaptic neuron

Neurotransmitter molecule

NT transporter

Synaptic vesicles

Voltage-gated sodium channel

GPCR (modulatory)

Ligand-gated ion channel

(direct excitation or

inhibition) +

+

Synapse between two neurons-

neurotransmission

Mechanism of neurotransmission

• Synaptic vesicles contain a neurotransmitter (NT) and release it when their membranes fuse with the outer cell membrane.

• Neurotransmitter molecules cross the synaptic cleft and bind to receptors known as ligand-gated ion channels (LGICs)

and G-protein–coupled receptors (GPCRs) on the postsynaptic neuron.

• GPCRs on the presynaptic neuron’s axon terminal alter the function of voltage-gated ion channels and modulate

neurotransmitter release.

• Neurotransmitter transporters remove neurotransmitter molecules from the synaptic cleft so that they can be repackaged into vesicles

Receptors

Ionotropic

(ion-channel linked)

Metabotropic

(use second messengers)

GABA_A, GABA_C, iGlu Glycine,

Serotonin, Nicotinic Ach,

P2X

GABA_B, mGlu, Adrenaline, Noradrenaline, Glucagon, FSH, LH,

TSH, ADH, parathormone, growth-factors,

cytokines

Receptors

Receptor - ligand interaction

Receptor properties Ligands

Ligand binds in the core region of the 7 transmembrane helices

11-cis-retinal (in rhodopsin) Acetylcholine

Catecholamines

Biogenic amines (histamine, serotonine, etc.) Nucleosides and nucleotides

Leukotrienes, prostaglandins, prostacyclins, Thromboxanes

Short peptide ligands bind partially in the core region and to the external loops

Peptide hormones (ACTH, glucagon, growth hormone) Parathyroid hormone, calcitonin

Ligands make several contacts with the N-

terminal segment and the external loops hypothalamic glycoprotein releasing factors (TRH, GnRH)

Induce an extensive reorganization of an extended N-terminal segment

Metabotropic receptors for neurotransmitters (such as GABA and glutamate)

Ca²⁺-sensing receptors, for example on parathyroid cells, thyroidal C-cells (which secrete calcitonin) and on the renal Juxtaglomerular apparatus

Proteinase activated receptors Receptors for thrombin amd thrypsin

Ion channel receptors

• Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit

– Acetylcholin (Ach) Nicotinic R – Na⁺ channel

– GABA_A, GABA_C, Glycine – Cl^- channels (inhibitory role in CNS)

• Glutamate-activated cationic channels: (excitatory role in CNS), tetrameric stucture, 3 TM regions/subunit

– iGlu

• ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit

– P2X purinoreceptor

7-transmembrane-spanning receptors (7-TM)

• Class A: Rhodopsin-like

• Class B: Secretin family

• Class C: Glutamate and GABA (metabotropic)

• Frizzled

• Adhesion family

7-TM ligands

Class A

Prostaglandins Thromboxane Serotonine Dopamine Histamine

Catecholamines Ach (M)

Rhodopsin Melatonin Chemokines Bradykinin Somatostatin Opioid

vasopressin

Class B Glucagon GnRH PTH CRH

Class C Glutamate GABA

Sweet tastes Secretin

Frizzled Wnt

Hedgehog Bitter tastes

Adhesion

Chondroitin-sulfate

Nicotinic Ach receptor

• Pore formed from 5 subunits: 2a, b, g, d

• Opening: the 2a units are distorted

• Desensitization: in the open conformation the b, g, d

subunits become phosphorylated by Protein kinase

A and C

Neurotransmission

Ions

GTP a

Receptor

G-protein is activated

Effector protein

Intracellular messengers

G-protein subunits or intracellular messengers modulate ion channels Neurotransmitter

GTP b g Cytoplasm a

Plasma membrane

Neurotransmitter

Ion channel

Cytoplasm

Plasma membrane

Acetylcholine

b a

Ions pass through the pore

Binding site for neurotransmitter

Change in intracellular ion contrentration Five assembled subunits

(2×a + 3×b) of nAChR

Extracellular

Cytoplasmic

COOH NH₂

TM 1

TM 2

TM 3

TM 4 Extracellular

Cytoplasmic

Ligand binding site

Four hydrophobic transmembrane domain (TM1-4) One subunit of nAChR Nicotinic acetylcholine receptor (nAChR)

O

N O

CH₃

H₃C

H₃C

CH₃ Acetylcholine

↑ PLCb

↑ [Ca²⁺]

↑ MAP kinases

↓ M current ↓ Voltage-operated Ca²⁺ channels

↓ Adenylyl cyclase

↑ MAP kinases

↑ GIRK channels Extracellular

Cytoplasmic

Muscarinic acetylcholine receptor (mAChR)

Acetylcholine

M1, M3, M5 M2, M4

TM 1

TM 3

TM 5

TM 7 TM

2 TM

4 TM

6

Gq/11 Gi/0

TM 1

TM 3

TM 5

TM 7 TM

2 TM

4 TM

6

Adrenergic receptors

Receptor

Gi a2

Inhibition of transmitter release

Ca²⁺

Adenylyl cyclase

ATP cAMP

Smooth muscle relaxation Gq

a1

Smooth muscle contraction Ca²⁺

Phospholipase C

PIP₂

IP₃

DAG

Gs b

Heart muscle contraction Smooth muscle relaxation

Glycogenolysis

Adenylyl cyclase

ATP cAMP

Adrenalin, Noradrenalin

Blocking the neuromuscular transmission

a-Bungarotoxin:

• Snake venom (Bungarus multicinctus)

• Binds to the N-Ach receptor and inactivates Curare (tubocurarin):

• In South American plants Strychnos toxifera and Chondrodendron tomentosum

• Indians use as arrow poison

• Curare binds to the same place on the N-Ach receptor than Achetylcholin BUT channel doesn’t open

• Causes paralysis of breathing muscles

• Used as muscle relaxant in anaesthesia

• Antidote: Acetylcholinesterase inhibitors