Ligand-gated ion channels opened by 5-HT in molluscan neurones

1. 5-Hydroxytryptamine (5-HT) activated a fast (70 ms to half maximum) and desensitizing inward current through non-selective channels conducting predominantly monovalent cations in neurones of Helix aspersa. 2. α-Methyl-5-HT was equipotent with 5-HT in activating this current, but the known selective agonists at vertebrate 5-HT₃ receptors, 2-methyl-5-HT and arylbiguanides were ineffective (< 100 μM). 5-Methoxytryptamine which is inactive on vertebrate 5-HT₃ receptors was a very weak agonist. 3. The responses were antagonized by the specific vertebrate 5-HT₃ receptor blocker MDL-72222 (IC₅₀ = 1 μM), but were only weakly affected by ondansetron (10 μM). The 5-HT₂-type antagonist, ketanserin (< 5 μM), had no effect. The responses were also antagonized by the non-specific antagonists (+)-tubocurarine and strychnine. 4. Unitary currents through channels non-selective for monovalent cations, and with a conductance of 2pS, could be activated repeatedly by 5-HT or α-methyl-5-HT in outside-out patches from neurones exhibiting the fast 5-HT-activated current (I[5-HT](fast)), even in the presence of 500 μM GDP-[βS] in the recording pipette. This strongly supports direct-gating of these channels by 5-HT. The properties of these unitary currents resembled those of I[5-HT](fast). 5. The pharmacological properties of this molluscan 5-HT-operated, ligand-gated channel differed sufficiently from known vertebrate 5-HT₃-type receptors to suggest that it represents a new class of 5-HT receptor.