Human 5-HT3B -- Ser 276
|Rat Equivalent||Asn 272|
|Mouse Equivalent||Asn 272|
Mouse 5-HT3B receptor subunit was expressed in HEK-293 cells with the 5-HT3A subunit.
Homomeric 5-HT3A receptors have a higher sensitivity to block by picrotoxin than do 5-HT3A/B receptors. This study examined the determinants of picrotoxin sensitivity in 5-HT3 receptors. The mouse 5-HT3B N272 residue is a determinant of picrotoxin inhibition. When replaced by the equivalent residue in the 5-HT3A subunit the 5-HT3B N272T mutant enhanced picrotoxin sensitivity of heteromeric 5-HT3A/B receptors. However, the mutant receptors were not as sensitive to picrotoxin as were homomeric 5-HT3A receptors, suggesting that other residues within the 5-HT3B subunit contribute to the reduced picrotoxin sensitivity of heteromeric receptors. 5-HT3 sensitivity of the mutant heteromeric receptor was increased slightly compared to the wild type heteromeric receptor.
When this mutant was combined with V273T there was no additional increase in 5-HT potency, nor was there an increase in picrotoxin sensitivity.
The equivalent residue in the human 5-HT3B subunit is serine. The mouse 5-HT3B N272S mutation increased picrotoxin sensitivity, suggesting that this residue may contribute to a higher picrotoxin sensitivity in human heteromeric receptors.
|Receptor (mouse)||5-HT EC50 (mM)||PTX IC50 (mM)|
|5-HT3A Wild-Type||1.2 +/- 0.07||41.2 +/- 5.6|
|5-HT3A: S268A (S2'A)||1.0 +/- 0.03*||45.6 +/- 5.2|
|5-HT3A: T272F (T6'F)||0.9 +/- 0.09*||1900 +/- 300**|
|5-HT3A: L273T ( L 7'T)||2.0 +/- 0.05**||4.0 +/- 0.5**|
|5-HT3A/B Wild-Type||1.0 +/- 0.1||1135 +/- 131|
|5-HT3B: N272T (N6'T)||0.5 +/- 0.03**||213 +/- 24**|
|5-HT3B: N272S(N6'S)||0.4 +/- 0.01**||173 +/- 28**|
|5-HT3B: V273T (V7'T)||0.6 +/- 0.09**||866 +/- 35|
|5-HT3B: N272T, V273T (N6'T,V7'T)||0.4 +/- 0.01**||343 +/- 45**|
*Significantly different from the wild-type receptor (p<0.05)
**Significantly different from the wild-type receptor (p<0.01)
***Significantly different from the wild-type 5-HT3A receptor
Das P, Dillion GH. (2005) Molecular determinants of picrotoxin inhibition of 5-hydroxytryptamine type 3 receptors. The Journal of pharmacology and experimental therapeutics 314(1):320-8
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