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Glucose-mediated inhibition of calcium-activated potassium channels limits alpha-cell calcium influx and glucagon secretion


Dickerson MTMatthew T , Dadi PKPrasanna K , Altman MKMolly K , Verlage KRKenneth R , Thorson ASAriel S , Jordan KLKelli L , Vierra NCNicholas C , Amarnath GGautami , Jacobson DADavid A . American journal of physiology. Endocrinology and metabolism. 2019 1 29; ().


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