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Ion permeation and conduction in a human recombinant 5-HT₃ receptor subunit (h5-HT_3A)

A. M. Brown, A. G. Hope, J. J. Lambert and J. A. Peters

1. A human recombinant homo-oligomeric 5-HT₃ receptor (h5-HT_3A) expressed in a human embryonic kidney cell line (HEK 293) was characterized using the whole-cell recording configuration of the patch clamp technique.

2. 5-HT evoked transient inward currents (EC₅₀ = 3·4 µM; Hill coefficient = 1·8) that were blocked by the 5-HT₃ receptor antagonist ondansetron (IC₅₀ = 103 pM) and by the non-selective agents metoclopramide (IC₅₀ = 69 nM), cocaine (IC₅₀ = 459 nM) and (+)-tubocurarine (IC₅₀ = 2·8 µM).

3. 5-HT-induced currents rectified inwardly and reversed in sign (E_5-HT) at a potential of -2·2 mV. N-Methyl-D-glucamine was finitely permeant. Permeability ratios P_Na/P_Cs and P_NMDG/P_Cs were 0·90 and 0·083, respectively.

4. Permeability towards divalent cations was assessed from measurements of E_5-HT in media where Ca²⁺ and Mg²⁺ replaced Na⁺. P_Ca/P_Cs and P_Mg/P_Cs were calculated to be 1·00 and 0·61, respectively.

5. Single channel chord conductance () estimated from fluctuation analysis of macroscopic currents increased with membrane hyperpolarization from 243 fS at -40 mV to 742 fS at -100 mV.

6. Reducing [Ca²⁺]_o from 2 to 0·1 mM caused an increase in the whole-cell current evoked by 5-HT. A concomitant reduction in [Mg²⁺]_o produced further potentiation. Fluctuation analysis indicates that a voltage-independent augmentation of contributes to this phenomenon.

7. The data indicate that homo-oligomeric receptors composed of h5-HT_3A subunits form inwardly rectifying cation-selective ion channels of low conductance that are permeable to Ca²⁺ and Mg²⁺.

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