Membrane depolarization and calcium influx induce glucagon gene transcription in pancreatic islet cells through the cyclic AMP-responsive element.
Glucagon-producing pancreatic islet cells generate calcium-dependent action potentials. By the control of calcium influx through voltage-gated calcium channels, calcium is a tightly regulated second messenger in these cells. It is unknown whether calcium is a signal for glucagon gene transcription. Therefore, rat glucagon reporter fusion genes were transiently transfected into pancreatic islet cell lines. High potassium-induced membrane depolarization activated glucagon gene transcription. The effects of a calcium chelator, calcium channel blockers, calmodulin antagonists, and an inhibitor of calcium/calmodulin-dependent protein kinase II (CaM kinase II) indicate that depolarization-induced glucagon gene transcription depends on calcium influx and CaM kinase II. The depolarization-responsive element was mapped to the glucagon cAMP-responsive element (CRE). The CRE-binding protein CREB was shown, by using GAL4-CREB fusion proteins, to function as a depolarization-regulated transcription factor in pancreatic islet cells. Membrane depolarization and cAMP had synergistic effects on glucagon gene transcription. These results suggest that rat glucagon gene transcription is regulated by membrane electrical activity and calcium influx in pancreatic islet cells. This signal may be transmitted via CaM kinase II and CREB to the glucagon CRE.
Department of Biochemical Pharmacology, University of Goettingen, Germany.
M
M
Schwaninger
G
G
Lux
R
R
Blume
E
E
Oetjen
H
H
Hidaka
W
W
Knepel
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005934:Glucagon / Q000235:genetics*; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000378:metabolism* / Q000502:physiology; D008564:Membrane Potentials; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D005934:Glucagon; D000242:Cyclic AMP; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium