Membrane lecture 7

Question 1

Ionotropic glutamate receptors

Answer 1

• Ligand-gated ion channels

- Functions in brain, when things go wrong → disease

Question 2

Classification

Answer 2

• uglu, slower responses
• 4 main families = alpha, kainate, NMDA, orphan
• In vivo, Glu opens for all

Question 3

iGluR structure

Answer 3

• Tetrameric w/ 4-fold symmetry
• Extracellular portion = dimer of dimers
• Ligand binding domain
• Homologue to KcsA

Mechanism (in closed state shut, Glu binds cleft triggers channel to open, D2 close, M3 move into open state)

Question 4

Structural data

Answer 4

• Physiological + x-ray structures
• MD simulations (App state)
• Different flexibility to different agonists
• Many structures solved as dimers w/ Gly+Thr linker rather than whole Tm

Question 5

Open state

Answer 5

• CT2 blocks desensitisation, trap in open/closed

- btw EC + TM region = ↑ dynamic, hard to resolve

Question 6

Overall motion

Answer 6

• Glu receptor solved in open + closed, 10A
• Resting → open = contraction of receptor, twisting motion
• Dimer interface = important
• Block w/ cyclothiazide
• Use in therapy

Question 7

RNA editing

Answer 7

• Alternative splicing at ‘flip flop’ site
• Affects desensitisation
• Q/R site
• R/G editing

Question 8

NMDA receptor

Answer 8

• Only active under certain conditions
• High permeability to Ca2+
• 2 agonists to open
• Receptor = hetramer
• GluNI can make functional channels
• NMDA receptors have at least 6 regulatory sites for ligands
• Glutamate more effect than NMDA
• Important in learning
• Agonist used in Alzheimers
• Signal to noise hypothesis