Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Pancreatic β-Cells

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels mediate the pacemaker current (Ih or If) observed in electrically rhythmic cardiac and neuronal cells. Here we describe a hyperpolarization-activated time-dependent cationic current, β-Ih, in pancreatic β-cells. Transcripts for HCN1–4 were detected by RT-PCR and quantitative PCR in rat islets and MIN6 mouse insulinoma cells. β-Ih in rat β-cells and MIN6 cells displayed biophysical and pharmacological properties similar to those of HCN currents in cardiac and neuronal cells. Stimulation of cAMP production with forskolin/3-isobutyl-1-methylxanthine (50 μm) or dibutyryl-cAMP (1 mm) caused a significant rightward shift in the midpoint activation potential of β-Ih, whereas expression of either specific small interfering (si)RNA against HCN2 (siHCN2b) or a dominant-negative HCN channel (HCN1-AAA) caused a near-complete inhibition of time-dependent β-Ih. However, expression of siHCN2b in MIN6 cells had no affect on glucose-stimulated insulin ...