Ligand-Gated Ion Channels

What are the essential functions of ion channels?

→ transport ions across membranes

→ regulate membrane potentials eg nerve and muscle cells for high speed communication

→ Ca2+ influx into the cytoplasm

What are the main structural features of all ion channels?

→ transmembrane proteins made up of two or more alpha helices that cross the lipid bilayer

→ made up of two to six subunits that surround the ‘pore’

→ they are classified into subgroups based on gating mechanism and ion selectivity

What is the structure of a simple ion channel?

→ TM helicase structures form a p-loop/pore that is highly selective to size/charge

→ on the cytoplasmic side - TMs more tightly packed creating a gate

→ when the gate is opened, force opens up the membrane to allow the ions through

→ membrane potential, mechanical stress and ligands will control this gate

→ 4 subunits, 2 helices and functions for secretion and absorption of fluids

What are the functions of voltage gated ion channels?

→ Na+ and K+ create action potentials in the excitable cell

→ Ca2+ is transported into he cytoplasm with 2nd messenger elicits a cellular response

What is the structure of voltage gated ion channels?

→ similar to simple ion channel but they have an additional S1 and S4 helices to form a voltage sensing domain lateral to subunits

→ large polypeptides extend into cytoplasm giving stability

→ plugging mechanism can close the gate

→ 4 subunits, 6-24 helices, functions for excitable cells

How are transient receptor potential channels similar to voltage gated ion channels?

→ share common structural features but evolved to sense chemicals and physical stimuli so no voltage sensing domain

→ functions for hot/spicy taste

How are ligand-gated ion channels similar to voltage gated ion channels?

→ similar in structure but controlled by the binding of a ligand, either intracellularly or extracellularly

→ no plugging mechanism and functions for cAMP and calmodulin signalling

What are the families of ionotropic receptors?

→ trimeric - ATP P2X receptor family - 3 subunits

→ tetrameric - Glutamate receptor family - 4 subunits

→ pentameric - Nicotinic receptor super family - 5 subunits

What is the structure of a pentameric receptor?

→ eg nAChR

→ 5 subunits - each has 4 transmembrane segments (M1, M2, M3, M4)

→ large external facing N domain and intracellular loop between M3 and M4. M2 lines the pore

Can there be different subunit combinations?

→ yes, they make up receptors in different parts of the brain

→ complexity provides diversity and opportunity for drug targeting

→ nAChalpha4 is involved in reward pathways and nicotine addiction

What combination of nAChRs have the highest affinity to nicotine?

→ alpha 4 beta 2 - abundantly expressed in the cortex and hippocampus

→ chronic exposure leads to receptor upregulation

What does a mutation in nAChR cause?

→ autosomal dominant nocturnal frontal lobe epilepsy - ADNFLE

→ mutation in M2 region of human alpha4 nictotinic subunit

→ enhanced receptor function = increased nicotinic-mediated transmitter release = ADNFLE seizures

→ delayed rising phase due to slow unblocking of closed receptors

What is the function of glutamate receptors?

→ main neurotransmitter in the brain

→ tetramer

→ form as dimmer of dimers, ligand binding site is in a cleft that ‘closes’ when occupied

→ vital to every aspect of brain function

What are the type of glutamate receptors?

→ AMPA receptors = mediate fast excitatory synaptic transmission in CNS

→ NDMA - N-methyl-D-aspartame receptor = learning and memory - slower than other isoforms

→ Kainate = similar to AMPA but less at synapses, linked to schizophrenia, depression and Huntingtons

What are the functional consequences of RNA processing in the AMPA subunits?

→ each subunit exists as two policing isoforms - flip and flop

→ due to alternative splicing of two exons in primary transcript, different domains in extracellular loop

→ different kinetic properties

→ flop has faster desensitisation rate and reduced current responses to glutamate than flip

What is the effect of the GluA2 Q/R site on Ca2+ channel permeability?

→ located inside the channel pore, in M2

→ when CAG (glutamine) codon is changed to CGG (arginine), mice prone to seizures and early death

→ they lacked the enzyme responsible for RNA editing

What happens when NMDA receptor is dysfunctional?

→ excess stimulation of NMDA in stroke leads to neuron death

→ receptor is important for controlling synaptic plasticity and mediating learning and memory functions

What is the structure of P2X receptors?

→ trimeric assembly - 3 subunits with 2 TM helices

→ ATP-gated ion channel

→ large extracellular domain, widely expressed receptor

→ 3 ATP molecules needed to open channe;

→ P2X 1-7 subtypes of subunits

What disease can occur due to a dysfunctional P2X receptor?

→ P2X2 - hearing loss

→ P2X4 - pain

→ P2X7 - inflammation, neurodegenerative disease