Membrane lecture 6

Question 1

Cys loop family receptor summary

Answer 1

• Shared topology
• Found mostly in neuromuscular synapses and brain
• Associated w/ ↑ disease
• Excitatory/cation selective or inhibitory/anion selective

Question 2

Structure of AchR

Answer 2

• 5 subunits w/ 3 distinct regions (EC, TM + IC)
• Muscle have 2a,y,gamma + B, Neuronal = mostly 3B +2a
• EC = 4TM per subunit, IC loop btw M3 + M4, M4 faces lipid, M2 lines pore
• Acetyl choline binds btw a+b, a+y interface
• Ach bs = ABC + EDF, different segments
• Cys loop = btw 2 lys
• Mutation of M2 helices

Question 3

ELIC/GLIC

Answer 3

• 3.4A GLIC
• Similar to nACHr
• GLIC opened at low pH
• ELIC has more occlusion by Phe or Leu

GluCI = glutamate-gated chloride channel, anion selective, ambiguous conformation
SHT3 = crystallised w/ Ab
GABA B3 = closed, B3 x physiological
GlyR = solved w/ cryo-EM, has 2 gates, when channel opens, radius is large enough to allow ion through

Question 4

How to know closed state

Answer 4

• nAChr has hydrophobic section near 9’ region
• Narrow point, r=3.1A, appears open
• Narrow pore means water x pass
• As ↑ radius, ↑ chance of fully open channel
• Ir could add dipoles to pore-lining surface
• Opening = overlay ELIC + GLIC, quaternary twist

Question 5

Why bacterial channels x help

Answer 5

• ECD of ELIC suggests AchBP = basal state, most have agonist bound
• Conf of TMS of nACHR EM is closer to GLIC than ELIC → active state?
• ELIC = unusual

Question 6

Lipids influence nACHR

Answer 6

• As ↑ cholesterol, ↑ stabilisation in resting state

- If no anionic lipids, nachR stabilised in desensitised state

Question 7

Receptor responses can be ‘tuned’

Answer 7

• Different sequences of receptor affect response to agonist in different ways
• Achieved w/ alternative splicing
• Editing = in critical position

Question 8

Disease

Answer 8

• SCS, atrophy of muscle, prolonged channel activation