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Evolutionary History of Ion Channels andNeurotransmitters
Neuro Journal Club, 06.03.08Peter HANTZ, Arendt Laboratory
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Voltage, and voltage/intracellular ligand-gated ion channlesK+
VG: fastly and slowly activated, inward rectifier, leak-channels
V/ILG: Ca-activated, ATP-activated, cyclic-nucleotide gated
Ca+VG: High voltage activated, Low voltage activatedV/ILG: Ca-activated, IP3 activated
Na+, Cl-, H+: mostly VG
Types of Ion Channels
Stretch-activated ion channelsLarge-conductance MScLow-conductance MSc
Light-gated ion channels
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Neurotransmitter systemsIonotropic receptors: (ligand-gated ion channels)Cys-loop receptors "fast activating"
Anionic(inhibitory)Gly, GABA
Cationic(excitatory)5HT, Ach (nicotinic)
Glutamate Gated ChannelsGlutamate, agonists: AMPA, NMDA, kainate
G-protein coupled (metabotropic) receptorsACh, Glu (AMPA, KAIN, NMDA), GABA, 5-HT, DA, NE, ...Shortcut pathway, Second Messenger Cascade
Other neurotransmitter receptorspeptides, NO, CO
Types of Ion Channels/Receptors
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Precursors of the VG-like ion channels
small synthetic peptides:-fold into a-helixes-voltage: inserted into membranes-spontaneously build ion 5-7 mer channels
1-TM ion channels:Influenza M2 tetramer
2-TM ion channels:simplest K+ channels: KcsA, Kir (inwardly rectifier) tetramer
Present in all three domains of lifeNo voltage-sensitivity
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Gene fusion/duplication:1.-4. subunits containing six transmembrane crossings
S1-S4: voltage gatingS4: + charged voltage sensorS5, S6: conserved selectivity filter
KvAP
Voltage-sensitive Potassium Channels
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6TM-type channels
Voltage and cyclic nucleotide-gated channels:one-domain, 6TM homotetramers
Usual structure of Na and Ca channels: α1 subunits = four LINKED DOMAINS Each: six transmembrane elements
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Possible origins of the 6TM channels
Two rounds of gene duplications?
-Similarities: domains I and III; domains II and IV-Two-domain channels were identified (TPC)
They evolved from one-domain 6TM multimers?
Ca or Na-channels are more ancestral?
4-domain Ca-channel: already in yeast4-domain Na-channel: only in multicellular animals
not detected in protozoa, in plants
But: There is an ancestral bacterial 6TM homotetrameric Na-channel
Note: two types of "inactivation" mechanisms (following activation)"ball and chain" or "inactivation loop"
Cl channels: conservative, structurally distinct (10-12 domains)
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Evolution of the LG-like ion channels
Structure (Cys-loop "fast activating" channels):
Mostly: pentamers of 1-domain 4-TM proteins N-term extracellular domain: ligand binding site
Made of several unrelated proteins?
Homologs in bacteria
Ancient role: nutrient seeking? osmotic regulation?Now: intercellular communication
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Evolution of the LG-like ion channels
Ancient:ACh, 5HT and GABA
Gly derived from GABA despite Gly is "more simple"
Root:?
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Structure of the GPCR
Single, 7TM polypeptide
2 extracellular loops: transmitter binding site
2 intracellular loops: activate G-proteins
Two major groups:PLC-activating (IP3)cAMP decrease
Ev. connection between ionotropic (LGICh)and metabotropic (GPCR)receptors ?
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7-TM architecture in procaryotes:bacteriorhodopsins, no GPC...linkage to eucaryotic GPCR ? (disputed)
GPCR:Present in plants, fungi and animals: common ancestor, 1.2 Gy ago
Evolution of the GPCR
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