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Homomeric complexes of 5-HT3A receptor subunits form a ligand-gated ion channel. This assembly does not fully reproduce the biophysical and pharmacological properties of native 5-HT3 receptors which might contain the recently cloned 5-HT3B receptor subunit. In the present study, heteromeric assemblies containing human 5-HT3A and 5-HT3B subunits were expressed in HEK 293 cells to detail the functional diversity of 5-HT3 receptors. We designed patch-clamp experiments with homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors to emphasize the kinetics of channel activation and desensitization. Co-expression of the 5-HT3B receptor subunit reduced the sensitivity for 5-HT (5-HT3A receptor: EC50 3μM, Hill coefficient 1.8; 5-HT3AB receptor: EC50 25μM, Hill coefficient 0.9) and markedly altered receptor desensitization. Kinetic modeling suggested that homomeric receptors, but not heteromeric receptors, desensitize via an agonist-induced open-channel block. Furthermore, heteromeric 5-HT3AB receptor assemblies recovered much faster from desensitization than homomeric 5-HT3A receptor assemblies. Unexpectedly, the specific 5-HT3 receptor agonist mCPBG induced an open-channel block at both homomeric and heteromeric receptors. Because receptor desensitization and resensitization massively affect amplitude, duration, and frequency of synaptic signaling, these findings are evidence in favor of a pivotal role of subunit composition of 5-HT3 receptors in serotonergic transmission.

We have studied the effects of increases in isoflurane concentration on the EEG bispectral index (BIS) in 70 patients anaesthetized with isoflurane-nitrous oxide-sufentanil for major abdominal surgery. During surgery, baseline BIS was recorded at 0.8% end-tidal isoflurane with nitrous oxide in oxygen (FIO2 0.35). After this, end-tidal isoflurane was increased to 1.6% for 15 min and decreased subsequently to 0.8% for 20 min to assess recovery. In 20 patients, BIS decreased from a mean value of 40 (SD 9) during baseline to 25 (10) at 1.6% isoflurane. In contrast, BIS did not change in 23 patients and increased in 27 patients from 35 (6) to 46 (8) as isoflurane was increased to 1.6%. In all patients, BIS recovered to baseline values at 0.8% isoflurane. The changes in BIS with increasing isoflurane concentration were not related to drugs or differences in physiological variables, which did not differ between groups. Patients with a decrease in BIS were significantly younger (38 (range 18-68) yr) than those with unchanged (55 (26-70) yr) or increased (60 (40-70) yr) BIS values (P < 0.001). It is possible that the paradoxical increase in BIS is related to continuous pre-burst EEG patterns consisting of high-frequency activity. This suggests that the use of BIS as a guide for isoflurane administration may be misleading in some patients undergoing surgical procedures.