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
EXTRACELLULAR RECEPTORS
ION CHANNELS
Tímea Berki and Ferenc Boldizsár Signal transduction
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Scheme of the signal transduction of cell surface receptors
Ligand Receptor
Intracellular signaling
Gene expression
Biological response
Receptor families
• Extracellular receptors: hidrophylic ligands eg. peptide, protein hormones
– Ion-channel receptors
– 7-transmembrane-spanning receptors (7TM) – Catalytic receptors: intrinsic enzyme activity
– Non-catalytic receptors: use cytoplasmic tyrosine kinases
• Intracellular receptors: lipophilic hormones eg. steroids, thyroxin
ENZYME-LINKED RECEPTORS G-PROTEIN-LINKED RECEPTORS ION-CHANNEL-LINKED RECEPTORS
Ions
Signal molecule
Cytoplasm Plasma membrane
GDP b g a
GTP b g a
b g
Enzyme Enzyme Enzyme
GTP a Signal molecule
G-protein Activated G-protein Activated enzyme
Dimer of signal molecule
Inactive catalytic domain
Enzyme Active catalytic
domain
Signal molecule
Activated enzyme
Extracellular receptor types
Receptors
Ionotropic
(ion-channel linked)
Metabotropic
(use second messengers)
GABAA, GABAC, iGlu Glycine,
Serotonin, Nicotinic Ach,
P2X
GABAB, mGlu, Adrenaline, Noradrenaline, Glucagon, FSH, LH,
TSH, ADH, parathormone, growth-factors,
cytokines
Receptors
Glucagon Secretin Adrenaline
ACTH LH FSH
Adenylyl cyclase
ATP cAMP
More receptors using the same
second messenger system
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, serotomine, 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
Functional groups of ligands
Inactive state Active state
R r
R
r r R
Inverse agonists Agonists
Partial agonists and antagonists
channels)
Ions
Ligand
Cytoplasm
Plasma membrane
Ligand gated ion channel
Ion channel receptors
• Cys-loop receptors: pentameric structure, 4 transmembrane (TM) regions/subunit
– e.g., Acetylcholin (Ach) Nicotinic R – Na+ channel
– e.g., GABAA, GABAC, Glycine – Cl- channels (inhibitory role in CNS)
• Glutamate-activated cationic channels: (excitatory role in CNS), tetrameric stucture, 3 TM regions/subunit
– e.g., iGlu
• ATP-gated channels: 3 homologous subunits, 2 TM regions/subunit
– e.g., P2X purinoreceptor
Nicotinic Ach receptor
TOP
FRONT
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
The axon terminal
Axon of motor neuron
Terminal button
Axon terminal
Voltage-gated Na+ channel
Acetylcholine
Muscle fiber Na+
Ca2+
Voltage-gated Ca2+ channel
Acetylcholinesterase
Vesicle of acethylcholine
K+ Neurotransmitter-gated
channel
Motor end plate
1
2
3
4 5 6
7
~4x107 nicotinic Ach Rs / end plate
Electric organs in animals
• Marine ray Torpedo
• Freshwater electric eel Electrophorus
• 2x10
11nicotinic Ach receptors/end plate!
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
Acetylcholinesterase (AchE)
• Quick removal of Ach from the synaptic space
• Ach → choline+acetyl
• Reversible inhibitors: therapeutic use (myasthenia, glaucoma, Alzheimer’s)
• Irreversble inhibitors: chemical weapons and pesticides e.g.
organophosphates
Ach
AchE