Evolutionary History of Ion Channels andNeurotransmitters

Neuro Journal Club, 06.03.08Peter HANTZ, Arendt Laboratory

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

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

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

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

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

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)

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

Evolution of the LG-like ion channels

Ancient:ACh, 5HT and GABA

Gly derived from GABA despite Gly is "more simple"

Root:?

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 ?

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