Human 5-HT3A -- Arg 219

Species Original Mutated to Mutation
Human Arg 219 Lys,Gln

R219K,R219Q

Rat Equivalent Gln 218    
Mouse Equivalent Lys 224 Arg K224R

 

hArg219Lys

When the triplet mutation of hM223I, hE224D and hS225I was also combined with hY217Q and hR219K, there was a 26-fold increase in the IC50 of (+)-Tubocurarine relative to the human wild type. When this quintuple mutation was combined with hY228S and hV237I, there was a further decrement of 2-fold of the IC50 value of (+)-Tubocurarine relative to the quintuple mutant.

 

Hope AG, Belelli D, Mair ID, Lambert JJ, Peters JA (1999) Molecular Determinants of (+)- Tubocurarine Binding at Recombinant 5-Hydroxytryptamine3A Receptor Subunits. Molecular Pharmacology 55:1037-1043

 

hArg219Gln

The mutation was made in the human 5-HT3A subunit at Arg219. This residue was numbered Arg196 in the paper in which numbering began at the end of the signal sequence.

In order to identify the potency of meta-chlorophenylbiguanide (mCPBG) in human 5-HT3A receptors, the recombinant human and rat 5-HT3A receptors were expressed in Xenopus Oocytes by cRNA injection and 5-HT-evoked currents were recorded using two-electorde voltage-clamp. The effect of replacing human Leu215, Pro216, Tyr217, Arg219, Met223, Ser225 and Tyr228 (numbering from the beginning of the signal sequence) by the equivalent residues (Phe, Thr, Lys,Gln, Ile, Thr and Ser) in the rat was to increase the potency of mCPBG as an agonist at the mutant human 5-HT3A receptor by 13-fold.

Mochizuki S.,Miyake A.,Furuichi K. (1999) Identification of a domain affecting agonist potency of meta-chlorophenylbiguanide in 5-HT3 receptors. European Journal of Pharmacology 369:125-132

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mLys224Arg

In a single point mutation of K224R, the IC50 value for (+)- Tubocurarine was indistinguishable from the wildtype.

When the triplet mutation of mI228M, mD229E and mI230S was also combined with mQ222Y and mK224R there was a 54-fold decrease in the IC50 of (+)-Tuocurarine relative to the mouse wild type. When this quintuple mutation was combined with mS233Y and mI242V, there was a further increment of 3-fold of the IC50 value of the (+)-Tubocurarine relative to the quintuple mutant.

Hope AG, Belelli D, Mair ID, Lambert JJ, Peters JA (1999) Molecular Determinants of (+)- Tubocurarine Binding at Recombinant 5-Hydroxytryptamine3A Receptor Subunits. Molecular Pharmacology 55:1037-1043

 

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