PHYSIOLOGICAL AND PHARMACOLOGICAL PROPERTIES OF 5-HT3 RECEPTORS - A PATCH CLAMP-STUDY

Whole cell and patch clamp techniques were used to investigate the properties of 5-HT3 receptors of a murine neuroblastoma cell line (Nl E-1 15) and adult rabbit nodose ganglion neurones. In addition, some preliminary results from guinea-pig nodose ganglion neurones are presented. In such cells, voltage-clamped at -60mV, 5-HT (10-mu-M) induced an inward current associated with a conductance increase. The results of ion substitution experiments suggest that the 5-HT activated ion channel is permeable to both Na+ and K+ ions with a permeability ratio (P(Na)/P(K)) of 0.94 and 0.92 for rabbit nodose ganglion cells and NlE-115 cells respectively. On outside out membrane patches excised from rabbit nodose ganglion neurones, 5-HT (1-mu-M) activated clearly discernible single channel currents with a conductance of 16.6 +/- 0.7 pS (n = 4). In contrast, fluctuation analysis of 5-HT induced whole cell currents suggests that the single channel conductance of NlE-115 cells is only 0.3 pS, a value some 50 fold lower. The 5-HT-induced whole cell currents recorded from all three preparations were antagonised by the selective 5-HT3 receptor antagonist ondansetron (GR38032F) and by the less selective agents metoclopromide, cocaine and (+)-tubocurarine. However, these preparations demonstrate a differential sensitivity to some antagonists. In particular, (+)-tubocurarine was a potent antagonist in NlE-115 cells (IC50 = 0.85nM) but was approximately 200 fold (IC50 = 156nM) and 1200 fold (IC50 = 10-mu-M) less potent in rabbit and guinea-pig nodose ganglion neurones respectively. Additionally, a novel effect of ketamine (10-mu-M) to potentiate the 5-HT-induced current of rabbit nodose ganglion neurones is described.