TABLE 4

Functional cooperativity factors (logβ) for allosteric modulators at mGlu5-wt and mutants derived from operational model analysis of interactions with glutamate

Data represent the mean ± S.E.M. from 4–8 independent experiments performed in duplicate.

MutationVU0360172 (Nicotinamide)VU0403602 (Picolinamide)VU0360173 (Nicotinamide)VU0405398 (Picolinamide)VU0415051 (Nicotinamide)VU0405386 (Picolinamide)
R5-wt (poly)0.37 ± 0.050.61 ± 0.080.17 ± 0.040.37 ± 0.040.40 ± 0.020.55 ± 0.07
R647A0.44 ± 0.130.60 ± 0.090.26 ± 0.030.38 ± 0.050.41 ± 0.110.58 ± 0.06
I650A0.58 ± 0.050.55 ± 0.08N.D.0.51 ± 0.08N.D.0.56 ± 0.08
G651F0.54 ± 0.070.79 ± 0.05No PAM0.43 ± 0.040.32 ± 0.050.70 ± 0.07
P654S0.26 ± 0.010.56 ± 0.05<50.34 ± 0.080.22 ± 0.100.32 ± 0.05
P654F0.25 ± 0.040.58 ± 0.14No PAM0.17 ± 0.040.66 ± 0.09*0.53 ± 0.09
S657CN.D.0.82 ± 0.15N.D.0.43 ± 0.150.55 ± 0.010.56 ± 0.12
Y658VNo PAMNo PAMNo PAMNAMNo PAMNo PAM
P742S0.87 ± 0.10*1.23 ± 0.06*0.69 ± 0.07*0.70 ± 0.150.92 ± 0.08*1.12 ± 0.17*
L743V0.36 ± 0.140.60 ± 0.060.43 ± 0.030.54 ± 0.080.36 ± 0.040.80 ± 0.03
N746A0.62 ± 0.040.67 ± 0.04N.D.0.57 ± 0.05N.D.0.63 ± 0.02
T780ANo PAM0.77 ± 0.08No PAM0.19 ± 0.01−0.28 ± 0.02*0.39 ± 0.04
W784A0.90 ± 0.14*1.05 ± 0.11*0.41 ± 0.100.48 ± 0.090.88 ± 0.10*0.66 ± 0.15
V788A0.57 ± 0.100.68 ± 0.090.66 ± 0.12*0.47 ± 0.050.53 ± 0.060.56 ± 0.11
F792A0.66 ± 0.120.97 ± 0.100.29 ± 0.110.73 ± 0.320.29 ± 0.020.85 ± 0.16
S806AN.D.N.D.N.D.N.D.N.D.0.79 ± 0.13
S808A0.50 ± 0.060.57 ± 0.10*No PAMNAM0.22 ± 0.02Neutral
S808T0.46 ± 0.060.76 ± 0.120.28 ± 0.070.34 ± 0.040.41 ± 0.040.45 ± 0.06
A809V0.60 ± 0.070.58 ± 0.09No PAMNo PAM0.37 ± 0.070.58 ± 0.11
A809G0.55 ± 0.041.29 ± 0.07*0.41 ± 0.070.70 ± 0.030.78 ± 0.12*1.12 ± 0.17*
C815A1.17 ± 0.12*1.29 ± 0.10*0.66 ± 0.06*0.75 ± 0.240.86 ± 0.05*1.38 ± 0.14*
  • N.D., not determined; No PAM, no observed positive allosteric modulation.

  • * P < 0.05 vs. wild-type value, one-way analysis of variance (ANOVA), Dunnett’s post-test.