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Characterization of a Ca²⁺-activated K⁺ current in insulin-secreting murine TC-3 cells

J. Ashot Kozak, Stanley Misler * and Diomedes E. Logothetis

1. The whole-cell perforated-patch recording mode was used to record a Ca²⁺-dependent K⁺ current (I_K(Ca)) in mouse TC-3 insulin-secreting cells.

2. Depolarizing voltage steps (to potentials where Ca²⁺ currents are activated) evoked a slowly activating, outward current, which exhibited a slow deactivation (in seconds) upon subsequent hyperpolarization.

3. This current was shown to increase with progressively longer depolarizing voltage steps. It could be reversibly abolished by the removal of Ca²⁺ from the external medium or by application of Ca²⁺ channel blockers, such as Cd²⁺ and nifedipine. It was concluded that the depolarization-evoked current was activated by Ca²⁺.

4. Variations in external K⁺ concentration led to shifts in the reversal potential of the Ca²⁺-dependent current as predicted by the Nernst equation for a K⁺-selective current.

5. The Ca²⁺-activated K⁺ current was insensitive to external TEA (10 mM), a concentration sufficient to block the large-conductance Ca²⁺-dependent (maxi-K_Ca) channel in -cells. It was also insensitive to apamin, tubocurarine and scyllatoxin (leiurotoxin I), specific blockers of small-conductance K_Ca channels.

6. The current was blocked by quinine, a non-specific K_Ca channel blocker and, surprisingly, by charybdotoxin (ChTX; 100 nM) but not iberiotoxin, a charybdotoxin analogue, which blocks the maxi-K_Ca channel. It was sensitive to block by clotrimazole and could be potently and reversibly potentiated by micromolar concentrations of niflumic acid. Thus, the current exhibited unique pharmacological characteristics, not conforming to the known K_Ca channel classes.

7. The ChTX-sensitive K_Ca channel was permeable to Tl⁺, K⁺, Rb⁺ and NH₄⁺ but not Cs⁺ ions.

8. The ChTX-sensitive I_K(Ca) could be activated by the muscarinic agonists in the presence or absence of external Ca²⁺, presumably by releasing Ca²⁺ from internal stores.

9. Acutely isolated porcine islet cells also exhibited a slow I_K(Ca) resembling that described in TC-3 cells in kinetic properties, insensitivity to TEA (5 mM) and sensitivity to quinidine, an analogue of quinine. The porcine I_K(Ca), however, was not sensitive to block by 100-200 nM ChTX. It is likely, that species differences account for pharmacological differences between the mouse and porcine slow I_K(Ca).

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