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Molecular determinants of Ca²⁺-dependent K⁺ channel function in rat dorsal vagal neurones

Paola Pedarzani, Anna Kulik *, Michael Müller *, Klaus Ballanyi * and Martin Stocker

1. Using in situ hybridisation histochemistry in combination with patch-clamp recordings and specific pharmacological tools, the molecular nature of the channels underlying Ca²⁺-dependent K⁺ currents was determined in dorsal vagal neurones (DVNs) of rat brainstem slices.

2. In situ hybridisation analysis at cellular resolution revealed the presence of 'big'-conductance Ca²⁺- and voltage-activated K⁺ (BK) channel -subunit mRNA, and of only one 'small'-conductance Ca²⁺-activated K⁺ (SK) channel subunit transcript, SK3, at very high levels in DVNs. By contrast, SK1 and SK2 mRNAs were below the threshold limit of detection.

3. The SK channel-mediated after-hyperpolarising current (I_AHP) was blocked by apamin with a half-maximal inhibitory concentration of ~2·2 nM. This is consistent with homomultimeric SK3 channels mediating I_AHP in DVNs. I_AHP was also blocked by scyllatoxin (20-30 nM) and curare (100-200 µM).

4. Application of apamin (100 nM) or scyllatoxin (20 nM) invariably caused a substantial increase to 146·1 ± 10·4 and 181·8 ± 12·9 % of control, respectively, in the spontaneous firing rate of DVNs. Action potential duration was not affected by these SK channel blockers.

5. The selective BK channel blocker iberiotoxin (50 nM) increased action potential duration by 22·5 ± 7·3 %, as did low concentrations of tetraethylammonium (0·5 mM; 99·3 ± 16·4 %) and the Ca²⁺ channel blocker Cd²⁺ (100 µM; 49·5 ± 20·9 %). BK channel blockade did not significantly affect the firing rate of DVNs.

6. These results allow us to establish a tight correlation between the properties of cloned and native BK and SK channels, and to achieve an understanding, at the molecular level, of their role in regulating the spontaneous firing frequency and in shaping single action potentials of central neurones.

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