Activation and desensitization of the 5-HT3 receptor in a rat glioma x mouse neuroblastoma hybrid cell.

1. Tight-seal voltage-clamp techniques were used to study the 5-HT3 receptor of differentiated NG108-15 cells. 2. The inward current caused by 5-HT was dependent on the 5-HT concentration: the apparent dissociation constant was 3.3 microM and the Hill coefficient was 1.8. 3. Immediately after establishing a recording, sustained application of a saturating concentration of 5-HT caused the response to decline with a half-time of 0.57 s (at a membrane potential of -70 mV). The time course of desensitization was best fitted by a sum of two exponentials. 4. Desensitization became slower during the first 10 min of recording in the whole-cell configuration, with the half-time for response decay increasing to 1.8 s. The deceleration of desensitization may result from wash-out of a cytoplasmic regulator of the receptor. 5. Desensitization declined less during whole-cell recordings when patch pipettes contained non-hydrolysable analogues of adenosine 5'-triphosphate. 6. Desensitization developed more rapidly following the addition of forskolin, prostaglandin E1, cholera toxin or 1,9-dideoxyforskolin to the recording medium. Non-hydrolysable adenosine 5'-phosphate analogues had no effect on the enhancement of desensitization induced by forskolin.