| First Author | Dickerson MT | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 316 |
| Issue | 4 | Pages | E646-E659 |
| PubMed ID | 30694690 | Mgi Jnum | J:275109 |
| Mgi Id | MGI:6303558 | Doi | 10.1152/ajpendo.00342.2018 |
| Citation | Dickerson MT, et al. (2019) Glucose-mediated inhibition of calcium-activated potassium channels limits alpha-cell calcium influx and glucagon secretion. Am J Physiol Endocrinol Metab 316(4):E646-E659 |
| abstractText | Pancreatic alpha-cells exhibit oscillations in cytosolic Ca(2+) (Ca(2+)c), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate alpha-cell Ca(2+)c oscillations have not been elucidated. As beta-cell Ca(2+)c oscillations are regulated in part by Ca(2+)-activated K(+) (Kslow) currents, this work investigated the role of Kslow in alpha-cell Ca(2+) handling and GCG secretion. alpha-Cells displayed Kslow currents that were dependent on Ca(2+) influx through L- and P/Q-type voltage-dependent Ca(2+) channels (VDCCs) as well as Ca(2+) released from endoplasmic reticulum stores. alpha-Cell Kslow was decreased by small-conductance Ca(2+)-activated K(+) (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca(2+)-activated K(+) (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca(2+)-activated K(+) (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of alpha-cell Kslow with apamin depolarized membrane potential ( Vm) (3.8 +/- 0.7 mV) and reduced action potential (AP) amplitude (10.4 +/- 1.9 mV). Although apamin transiently increased Ca(2+) influx into alpha-cells at low glucose (42.9 +/- 10.6%), sustained SK (38.5 +/- 10.4%) or BK channel inhibition (31.0 +/- 11.7%) decreased alpha-cell Ca(2+) influx. Total alpha-cell Ca(2+)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 alpha-cell Ca(2+)c following prolonged Kslow 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 Kslow activation provides a hyperpolarizing influence on alpha-cell Vm that sustains Ca(2+) entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when alpha-cell Ca(2+)c is elevated during secretagogue stimulation, Kslow activation helps to preserve GCG secretion. |
