Pancreatic α-cells exhibit oscillations in cytosolic Ca²⁺ (Ca²⁺_c), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca²⁺_c oscillations have not been elucidated. As β-cell Ca²⁺_c oscillations are regulated in part by Ca²⁺-activated K⁺ (K_slow) currents, this work investigated the role of K_slow in α-cell Ca²⁺ handling and GCG secretion. α-Cells displayed K_slow currents that were dependent on Ca²⁺ influx through L- and P/Q-type voltage-dependent Ca²⁺ channels (VDCCs) as well as Ca²⁺ released from endoplasmic reticulum stores. α-Cell K_slow was decreased by small-conductance Ca²⁺-activated K⁺ (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca²⁺-activated K⁺ (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca²⁺-activated K⁺ (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell K_slow with apamin depolarized membrane potential ( V_m) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca²⁺ influx into α-cells at low glucose (42.9 ± 10.6%), sustained SK (38.5 ± 10.4%) or BK channel inhibition (31.0 ± 11.7%) decreased α-cell Ca²⁺ influx. Total α-cell Ca²⁺_c was similarly reduced (28.3 ± 11.1%) following prolonged treatment with high glucose, but it was not decreased further by SK or BK channel inhibition. Consistent with reduced α-cell Ca²⁺_c following prolonged K_slow inhibition, apamin decreased GCG secretion from mouse (20.4 ± 4.2%) and human (27.7 ± 13.1%) islets at low glucose. These data demonstrate that K_slow activation provides a hyperpolarizing influence on α-cell V_m that sustains Ca²⁺ entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca²⁺_c is elevated during secretagogue stimulation, K_slow activation helps to preserve GCG secretion.

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